Substituted heterocycles as bromodomain inhibitors

ABSTRACT

The present application relates to substituted heterocycles compound of Formula I and pharmaceutical compositions thereof useful for the inhibition of BET protein function by binding to bromodomains (Formula I).

This application is a U.S. national stage entry under 35 U.S.C. § 371 ofInternational Application No. PCT/IB2015/002479, filed Dec. 11, 2015,which claims priority to U.S. Provisional Patent Application No.62/090,853, filed Dec. 11, 2014, all of which are hereby incorporated byreference in their entirety.

The invention provides novel compounds, pharmaceutical compositionscontaining such compounds, and their use in prevention and treatment ofdiseases and conditions associated with bromodomain and extra terminaldomain (BET) proteins.

Post-translational modifications (PTMs) of histones are involved inregulation of gene expression and chromatin organization in eukaryoticcells. Histone acetylation at specific lysine residues is a PTM that isregulated by histone acetylases (HATs) and deacetylases (HDACs).Peserico, A. and C. Simone, “Physical and functional HAT/HDAC interplayregulates protein acetylation balance,” J Biomed Biotechnol, 2011:371832(2011). Small molecule inhibitors of HDACs and HATs are beinginvestigated as cancer therapy. Hoshino, I. and H. Matsubara, “Recentadvances in histone deacetylase targeted cancer therapy” Surg Today40(9):809-15 (2010); Vernarecci, S., F. Tosi, and P. Filetici, “Tuningacetylated chromatin with HAT inhibitors: a novel tool for therapy”Epigenetics 5(2):105-11 (2010); Bandyopadhyay, K., et al.,“Spermidinyl-CoA-based HAT inhibitors block DNA repair and providecancer-specific chemo- and radiosensitization,” Cell Cycle 8(17):2779-88(2009); Arif, M., et al., “Protein lysine acetylation in cellularfunction and its role in cancer manifestation,” Biochim Biophys Acta1799(10-12):702-16 (2010). Histone acetylation controls gene expressionby recruiting protein complexes that bind directly to acetylated lysinevia bromodomains. Sanchez, R. and M. M. Zhou, “The role of humanbromodomains in chromatin biology and gene transcription,” Curr OpinDrug Discov Devel 12(5):659-65 (2009). One such family, the bromodomainand extra terminal domain (BET) proteins, comprises Brd2, Brd3, Brd4,and BrdT, each of which contains two bromodomains in tandem that canindependently bind to acetylated lysines, as reviewed in Wu, S. Y. andC. M. Chiang, “The double bromodomain-containing chromatin adaptor Brd4and transcriptional regulation,” J Biol Chem 282(18):13141-5 (2007).

Interfering with BET protein interactions via bromodomain inhibitionresults in modulation of transcriptional programs that are oftenassociated with diseases characterized by dysregulation of cell cyclecontrol, inflammatory cytokine expression, viral transcription,hematopoietic differentiation, insulin transcription, and adipogenesis.Belkina, A. C. and G. V. Denis, “BET domain co-regulators in obesity,inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012). BETinhibitors are believed to be useful in the treatment of diseases orconditions related to systemic or tissue inflammation, inflammatoryresponses to infection or hypoxia, cellular activation andproliferation, lipid metabolism, fibrosis, and the prevention andtreatment of viral infections. Belkina, A. C. and G. V. Denis, “BETdomain co-regulators in obesity, inflammation and cancer,” Nat RevCancer 12(7):465-77 (2012); Prinjha, R. K., J. Witherington, and K. Lee,“Place your BETs: the therapeutic potential of bromodomains,” TrendsPharmacol Sci 33(3):146-53 (2012).

Autoimmune diseases, which are often chronic and debilitating, are aresult of a dysregulated immune response, which leads the body to attackits own cells, tissues, and organs. Pro-inflammatory cytokines includingIL-1β, TNF-α, IL-6, MCP-1, and IL-17 are overexpressed in autoimmunedisease. IL-17 expression defines the T cell subset known as Th17 cells,which are differentiated, in part, by IL-6, and drive many of thepathogenic consequences of autoimmune disease. Thus, the IL-6/Th17 axisrepresents an important, potentially druggable target in autoimmunedisease therapy. Kimura, A. and T. Kishimoto, “IL-6: regulator ofTreg/Th17 balance,” Eur J Immunol 40(7):1830-5 (2010). BET inhibitorsare expected to have anti-inflammatory and immunomodulatory properties.Belkina, A. C. and G. V. Denis, “BET domain co-regulators in obesity,inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Prinjha,R. K., J. Witherington, and K. Lee, “Place your BETs: the therapeuticpotential of bromodomains,” Trends PharmacolSci 33(3):146-53 (2012). BETinhibitors have been shown to have a broad spectrum of anti-inflammatoryeffects in vitro including the ability to decrease expression ofpro-inflammatory cytokines such as IL-1β, MCP-1, TNF-α, and IL-6 inactivated immune cells. Mirguet, O., et al., “From ApoAI upregulation toBET family bromodomain inhibition: discovery of I-BET151,” Bioorg MedChem Lett 22(8):2963-7 (2012); Nicodeme, E., et al., “Suppression ofinflammation by a synthetic histone mimic,” Nature 468(7327):1119-23(2010); Seal, J., et al., “Identification of a novel series of BETfamily bromodomain inhibitors: binding mode and profile of I-BET151(GSK1210151A),” Bioorg Med Chem Lett 22(8):2968-72 (2012). The mechanismfor these anti-inflammatory effects may involve BET inhibitor disruptionof Brd4 co-activation of NF-κB-regulated pro-inflammatory cytokinesand/or displacement of BET proteins from cytokine promoters, includingIL-6. Nicodeme, E., et al., “Suppression of inflammation by a synthetichistone mimic,” Nature 468(7327):1119-23 (2010); Zhang, G., et al.,“Down-regulation of NF-kappaB Transcriptional Activity in HIVassociatedKidney Disease by BRD4 Inhibition,” J Biol Chem, 287(34):8840-51 (2012);Zhou, M., et al., “Bromodomain protein Brd4 regulates humanimmunodeficiency virus transcription through phosphorylation of CDK9 atthreonine 29,” J Virol 83(2):1036-44 (2009). In addition, because Brd4is involved in T-cell lineage differentiation, BET inhibitors may beuseful in inflammatory disorders characterized by specific programs of Tcell differentiation. Zhang, W. S., et al.,“Bromodomain-Containing-Protein 4 (BRD4) Regulates RNA Polymerase IISerine 2 Phosphorylation in Human CD4+ T Cells,” J Biol Chem (2012).

The anti-inflammatory and immunomodulatory effects of BET inhibitionhave also been confirmed in vivo. A BET inhibitor prevented endotoxin-or bacterial sepsis-induced death and cecal ligation puncture-induceddeath in mice, suggesting utility for BET inhibitors in sepsis and acuteinflammatory disorders. Nicodeme, E., et al., “Suppression ofinflammation by a synthetic histone mimic,” Nature 468(7327):1119-23(2010). A BET inhibitor has been shown to ameliorate inflammation andkidney injury in HIV-1 transgenic mice, an animal model forHIV-associated nephropathy, in part through inhibition of Brd4interaction with NF-κB. Zhang, G., et al., “Down-regulation of NF-kappaBTranscriptional Activity in HIV associated Kidney Disease by BRD4Inhibition,” J Biol Chem 287(34):8840-51 (2012). The utility of BETinhibition in autoimmune disease was demonstrated in a mouse model ofmultiple sclerosis, where BET inhibition resulted in abrogation ofclinical signs of disease, in part, through inhibition of IL-6 andIL-17. R. Jahagirdar, S. M. et al., “An Orally Bioavailable SmallMolecule RVX-297 Significantly Decreases Disease in a Mouse Model ofMultiple Sclerosis,” World Congress of Inflammation, Paris, France(2011). These results were supported in a similar mouse model where itwas shown that treatment with a BET inhibitor inhibited T celldifferentiation into pro-autoimmune Th1 and Th17 subsets in vitro, andfurther abrogated disease induction by pro-inflammatory Th1 cells.Bandukwala, H. S., et al., “Selective inhibition of CD4+ T-cell cytokineproduction and autoimmunity by BET protein and c-Myc inhibitors,” ProcNatl Acad Sci USA 109(36):14532-7 (2012).

BET inhibitors may be useful in the treatment of a variety of chronicautoimmune inflammatory conditions. Thus, one aspect of the inventionprovides compounds, compositions, and methods for treating autoimmuneand/or inflammatory diseases by administering one or more compounds ofthe invention or pharmaceutical compositions comprising one or more ofthose compounds. Examples of autoimmune and inflammatory diseases,disorders, and syndromes that may be treated using the compounds andmethods of the invention include but are not limited to, inflammatorypelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis,encephalitis, meningitis, myocarditis, nephritis (Zhang, G., et al.,“Down-regulation of NF-kappaB Transcriptional Activity in HIVassociatedKidney Disease by BRD4 Inhibition,” J Biol Chem 287(34):8840-51 (2012)),osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis,gingivitis, appendicitis, pancreatitis, cholecystitis,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis (Prinjha, R. K., J. Witherington, and K.Lee, “Place your BETs: the therapeutic potential of bromodomains,”Trends Pharmacol Sci 33(3):146-53 (2012)), Sjogren's disease, tissuegraft rejection, hyperacute rejection of transplanted organs, asthma,allergic rhinitis, chronic obstructive pulmonary disease (COPD),autoimmune polyglandular disease (also known as autoimmune polyglandularsyndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis,dermatomyositis, multiple sclerosis (Bandukwala, H. S., et al.,“Selective inhibition of CD4+ T-cell cytokine production andautoimmunity by BET protein and c-Myc inhibitors,” Proc Natl Acad SciUSA 109(36):14532-7 (2012)), scleroderma, vasculitis, autoimmunehemolytic and thrombocytopenic states, Goodpasture's syndrome,atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer'sdisease, Type I diabetes (Belkina, A. C. and G. V. Denis, “BET domainco-regulators in obesity, inflammation and cancer,” Nat Rev Cancer12(7):465-77 (2012)), septic shock (Zhang, G., et al., “Down-regulationof NF-kappaB Transcriptional Activity in HIVassociated Kidney Disease byBRD4 Inhibition,” J Biol Chem 287(34):8840-51 (2012)), systemic lupuserythematosus (SLE) (Prinjha, R. K., J. Witherington, and K. Lee, “Placeyour BETs: the therapeutic potential of bromodomains,” Trends PharmacolSci 33(3):146-53 (2012)), rheumatoid arthritis (Denis, G. V.,“Bromodomain coactivators in cancer, obesity, type 2 diabetes, andinflammation,” Discov Med 10(55):489-99 (2010)), psoriatic arthritis,juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenicpurpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease,uveitis, dry eye disease, scleroderma, mycosis fungoides, and Graves'disease.

BET inhibitors may be useful in the treatment of a wide variety of acuteinflammatory conditions. Thus, one aspect of the invention providescompounds, compositions, and methods for treating inflammatoryconditions including but not limited to, acute gout, nephritis includinglupus nephritis, vasculitis with organ involvement, such asglomerulonephritis, vasculitis, including giant cell arteritis,Wegener's granulomatosis, polyarteritis nodosa, Behcet's disease,Kawasaki disease, and Takayasu's arteritis.

BET inhibitors may be useful in the prevention and treatment of diseasesor conditions that involve inflammatory responses to infections withbacteria, viruses, fungi, parasites, and their toxins, such as, but notlimited to sepsis, sepsis syndrome, septic shock (Nicodeme, E., et al.,“Suppression of inflammation by a synthetic histone mimic,” Nature468(7327):1119-23 (2010)), systemic inflammatory response syndrome(SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acutelung injury, adult respiratory distress syndrome (ARDS), acute renalfailure, fulminant hepatitis, burns, post-surgical syndromes,sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis,malaria, and SIRS associated with viral infections, such as influenza,herpes zoster, herpes simplex, and coronavirus. Belkina, A. C. and G. V.Denis, “BET domain co-regulators in obesity, inflammation and cancer,”Nat Rev Cancer 12(7):465-77 (2012). Thus, one aspect of the inventionprovides compounds, compositions, and methods for treating theseinflammatory responses to infections with bacteria, viruses, fungi,parasites, and their toxins described herein.

Cancer is a group of diseases caused by dysregulated cell proliferation.Therapeutic approaches aim to decrease the numbers of cancer cells byinhibiting cell replication or by inducing cancer cell differentiationor death, but there is still significant unmet medical need for moreefficacious therapeutic agents. Cancer cells accumulate genetic andepigenetic changes that alter cell growth and metabolism, promoting cellproliferation and increasing resistance to programmed cell death, orapoptosis. Some of these changes include inactivation of tumorsuppressor genes, activation of oncogenes, and modifications of theregulation of chromatin structure, including deregulation of histonePTMs. Watson, J. D., “Curing ‘incurable’ cancer,” Cancer Discov1(6):477-80 (2011); Morin, R. D., et al., “Frequent mutation ofhistone-modifying genes in non-Hodgkin lymphoma” Nature476(7360):298-303 (2011).

One aspect of the invention provides compounds, compositions, andmethods for treating human cancer, including, but not limited to,cancers that result from aberrant translocation or overexpression of BETproteins (e.g., NUT midline carcinoma (NMC) (French, C. A., “NUT midlinecarcinoma,” Cancer Genet Cytogenet 203(1):16-20 (2010) and B-celllymphoma (Greenwald, R. J., et al., “E mu-BRD2 transgenic mice developB-cell lymphoma and leukemia,” Blood 103(4):1475-84 (2004)). NMC tumorcell growth is driven by a translocation of the Brd4 or Brd3 gene to thenutlin 1 gene. Filippakopoulos, P., et al., “Selective inhibition of BETbromodomains,” Nature 468(7327):1067-73 (2010). BET inhibition hasdemonstrated potent antitumor activity in murine xenograft models ofNMC, a rare but lethal form of cancer. The present disclosure provides amethod for treating human cancers, including, but not limited to,cancers dependent on a member of the myc family of oncoproteinsincluding c-myc, MYCN, and L-myc. Vita, M. and M. Henriksson, “The Myconcoprotein as a therapeutic target for human cancer,” Semin Cancer Biol16(4):318-30 (2006). These cancers include Burkitt's lymphoma, acutemyelogenous leukemia, multiple myeloma, and aggressive humanmedulloblastoma. Vita, M. and M. Henriksson, “The Myc oncoprotein as atherapeutic target for human cancer,” Semin Cancer Biol 16(4):318-30(2006). Cancers in which c-myc is overexpressed may be particularlysusceptible to BET protein inhibition; it has been shown that treatmentof tumors that have activation of c-myc with a BET inhibitor resulted intumor regression through inactivation of c-myc transcription. Dawson, M.A., et al., “Inhibition of BET recruitment to chromatin as an effectivetreatment for MLL-fusion leukaemia,” Nature 478(7370):529-33 (2011);Delmore, J. E., et al., “BET bromodomain inhibition as a therapeuticstrategy to target c-Myc,” Cell 146(6):904-17 (2010); Mertz, J. A., etal., “Targeting MYC dependence in cancer by inhibiting BETbromodomains,” Proc Natl Acad Sci USA 108(40):16669-74 (2011); Ott, C.J., et al., “BET bromodomain inhibition targets both c-Myc and IL7R inhighrisk acute lymphoblastic leukemia,” Blood 120(14):2843-52 (2012);Zuber, J., et al., “RNAi screen identifies Brd4 as a therapeutic targetin acute myeloid leukaemia,” Nature 478(7370):524-8 (2011).

Embodiments of the invention include methods for treating human cancersthat rely on BET proteins and pTEFb (Cdk9/CyclinT) to regulate oncogenes(Wang, S. and P. M. Fischer, “Cyclin-dependent kinase 9: a keytranscriptional regulator and potential drug target in oncology,virology and cardiology,” Trends Pharmacol Sci 29(6):302-13 (2008)), andcancers that can be treated by inducing apoptosis or senescence byinhibiting Bcl2, cyclin-dependent kinase 6 (CDK6) (Dawson, M. A., etal., “Inhibition of BET recruitment to chromatin as an effectivetreatment for MLL-fusion leukaemia,” Nature 478(7370):529-33 (2011)), orhuman telomerase reverse transcriptase (hTERT) (Delmore, J. E., et al.,“BET bromodomain inhibition as a therapeutic strategy to target c-Myc,”Cell 146(6):904-17 (2010); Ruden, M. and N. Puri, “Novel anticancertherapeutics targeting telomerase,” Cancer Treat Rev 39(5):444-456(2012)).

Inhibition of BET proteins may also result in inhibition of enhancerand/or super-enhancer known to drive transcriptional programs associatedwith several human disease etiologies (Hnisz, D. et al. “Super-enhancersin the control of cell identity and disease,” Cell 155:934-947 (2013);Loven, J. et al. “Selective inhibition of tumor oncogenes by disruptionof super-enhancers.” Cell 153: 320-334 (2013); Whyte, W. A. et al.“Master transcription factors and mediator establish super-enhancers atkey cell identity genes,” Cell 153:307-319 (2013)). The MYC oncogene isan example of a gene associated with a super enhancer that is disruptedby BET-bromodomain inhibitors. See, e.g., Loven (2013). Thus, one aspectof the invention provides compounds, compositions, and methods fortreating such diseases and disorders, including cancers associated witha super-enhancer or enhancer that may be disrupted with a BET inhibitor.

BET inhibitors may be useful in the treatment of cancers including, butnot limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma,acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia,acute erythroid leukemia, acute lymphoblastic leukemia (see, e.g., Loven(2013)), acute megakaryoblastic leukemia, acute monocytic leukemia,acute myeloid leukemia (Dawson, M. A., et al., “Inhibition of BETrecruitment to chromatin as an effective treatment for MLL-fusionleukaemia,” Nature 478(7370):529-33 (2011); Mertz, J. A., et al.,“Targeting MYC dependence in cancer by inhibiting BET bromodomains,”Proc Natl Acad Sci USA 108(40):16669-74 (2011); Zuber, J., et al., “RNAiscreen identifies Brd4 as a therapeutic target in acute myeloidleukaemia,” Nature 478(7370):524-8 (2011)), adenocarcinoma, adenoidcystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamouscarcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adultT-cell leukemia/lymphoma (Wu, X. et al. “Bromodomain and extraterminal(BET) protein inhibition suppresses human T cell leukemia virus 1(HTLV-1) Tax protein-mediated tumorigenesis by inhibiting nuclear factorkappaB (NF-kappaB) signaling,” J Biol Chem 288:36094-36105 (2013)),aggressive NK-cell leukemia, AIDS-related lymphoma, alveolarrhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma,anaplastic large cell lymphoma, anaplastic thyroid cancer,angioimmunoblastic T-cell lymphoma (Knoechel, B. et al. “An epigeneticmechanism of resistance to targeted therapy in T cell acutelymphoblastic leukemia,” Nat Genet 46:364-370 (2014); Loosveld, M. etal. “Therapeutic Targeting of c-Myc in T-Cell Acute LymphoblasticLeukemia (T-ALL),” Oncotarget 5(10):3168-72 (2014); Reynolds, C. et al.“Repression of BIM mediates survival signaling by MYC and AKT inhigh-risk T-cell acute lymphoblastic leukemia,” Leukemia 28(9):1819-27(2014); Roderick, J. E. et al. “c-Myc inhibition prevents leukemiainitiation in mice and impairs the growth of relapsed and inductionfailure pediatric T-ALL cells,” Blood 123:1040-1050 (2014)),angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoidtumor, B-cell acute lymphoblastic leukemia (Ott, C. J., et al., “BETbromodomain inhibition targets both c-Myc and IL7R in highrisk acutelymphoblastic leukemia,” Blood 120(14):2843-52 (2012)), B-cell chroniclymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma(Greenwald, R. J., et al., “E mu-BRD2 transgenic mice develop B-celllymphoma and leukemia,” Blood 103(4):1475-84 (2004)), basal cellcarcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer(Lamoureux, F. et al. “Selective inhibition of BET bromodomainepigenetic signalling interferes with the bone-associated tumour viciouscycle,” Nature Comm 5:3511 (2014), Brenner tumor, Brown tumor, Burkitt'slymphoma (Mertz, J. A., et al., “Targeting MYC dependence in cancer byinhibiting BET bromodomains,” Proc Natl Acad Sci USA 108(40):16669-74(2011)), breast cancer (Feng, Q. et al. “An epigenomic approach totherapy for tamoxifen-resistant breast cancer,” Cell Res 24:809-819(2014); Nagarajan, S. et al. “Bromodomain Protein BRD4 is Required forEstrogen Receptor-Dependent Enhancer Activation and Gene Transcription,”Cell Rep 8:460-469 (2014); Shi, J. et al. “Disrupting the Interaction ofBRD4 with Diacetylated Twist Suppresses Tumorigenesis in Basal-likeBreast Cancer,” Cancer Cell 25:210-225 (2014)), brain cancer, carcinoma,carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloidsarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma,clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-celllymphoma, cervical cancer, colorectal cancer, Degos disease,desmoplastic small round cell tumor, diffuse large B-cell lymphoma(Chapuy, B. et al. “Discovery and characterization ofsuper-enhancer-associated dependencies in diffuse large B celllymphoma,” Cancer Cell 24:777-790 (2013); Trabucco, S. E. et al.“Inhibition of bromodomain proteins for the treatment of human diffuselarge B-cell lymphoma,” Clin Can Res 21(1):113-122 (2015); Ceribelli, M.et al. “Blockade of oncogenic IkappaB kinase activity in diffuse largeB-cell lymphoma by bromodomain and extraterminal domain proteininhibitors,” PNAS 111:11365-11370 (2014)), dysembryoplasticneuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrinegland neoplasm, endodermal sinus tumor, enteropathy-associated T-celllymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma,follicular lymphoma, follicular thyroid cancer, ganglioneuroma,gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma,giant cell fibroblastoma, giant cell tumor of the bone, glial tumor,glioblastoma multiforme (Cheng, Z et al. “Inhibition of BET bromodomaintargets genetically diverse glioblastoma,” Clin Can Res 19:1748-1759(2013); Pastori, C. et al. “BET bromodomain proteins are required forglioblastoma cell proliferation,” Epigenetics 9:611-620 (2014)), glioma,gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma (Lwin, T. et al. “Amicroenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop innon-Hodgkin B cell lymphomas,” J Clin Invest 123:4612-4626 (2013)),invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngealcancer, lentigo maligna, lethal midline carcinoma, leukemia, Leydig celltumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma,lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acutemyelogenous leukemia (Mertz, J. A., et al., “Targeting MYC dependence incancer by inhibiting BET bromodomains,” Proc Natl Acad Sci USA108(40):16669-74 (2011)), chronic lymphocytic leukemia, liver cancer,small cell lung cancer, non-small cell lung cancer (Lockwood, W. W. etal. “Sensitivity of human lung adenocarcinoma cell lines to targetedinhibition of BET epigenetic signaling proteins,” PNAS 109:19408-19413(2012); Shimamura, T. et al. “Efficacy of BET bromodomain inhibition inKras-mutant non-small cell lung cancer,” Clin Can Res 19:6183-6192(2013)) MALT lymphoma, malignant fibrous histiocytoma, malignantperipheral nerve sheath tumor (Baude, A. et al. “PRC2 loss amplifies Rassignaling in cancer,” Nat Genet 46:1154-1155 (2014); Patel, A. J. et al.“BET bromodomain inhibition triggers apoptosis of NF1-associatedmalignant peripheral nerve sheath tumors through Bim induction,” CellRep 6:81-92 (2014)), malignant triton tumor, mantle cell lymphoma(Moros, A. et al. “Synergistic antitumor activity of lenalidomide withthe BET bromodomain inhibitor CP1203 in bortezomib-resistant mantle celllymphoma,” Leukemia 28:2049-2059 (2014)), marginal zone B-cell lymphoma,mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma ofthe breast, medullary thyroid cancer, medulloblastoma (Bandopadhayay, P.et al. “BET bromodomain inhibition of MYC-amplified medulloblastoma,”Clin Can Res 20:912-925 (2014); Henssen, A. G. et al. “BET bromodomainprotein inhibition is a therapeutic option for medulloblastoma”Oncotarget 4(11):2080-2089 (2013); Long, J. et al. “The BET bromodomaininhibitor I-BET151 acts downstream of Smoothened to abrogate the growthof Hedgehog driven cancers,” J Biol Chem 289(51):35494-35502 (2014);Tang, Y. et al. “Epigenetic targeting of Hedgehog pathwaytranscriptional output through BET bromodomain inhibition,” Nat Med20(7):732-40 (2014); Venataraman, S. et al. “Inhibition of BRD4attenuates tumor cell self-renewal and suppresses stem cell signaling inMYC driven medulloblastoma,” Oncotarget 5(9):2355-71 (2014)) melanoma(Segura et al, “BRD4 is a novel therapeutic target in melanoma,” CancerRes 72(8): Supplement 1 (2012)), meningioma, Merkel cell cancer,mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor,mixed lineage leukemia (Dawson, M. A., et al., “Inhibition of BETrecruitment to chromatin as an effective treatment for MLL-fusionleukaemia,” Nature 478(7370):529-33 (2011)), mucinous tumor, multiplemyeloma (Delmore, J. E., et al., “BET bromodomain inhibition as atherapeutic strategy to target c-Myc,” Cell 146(6):904-17 (2010)),muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma,myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma(Puissant, A. et al. “Targeting MYCN in neuroblastoma by BET bromodomaininhibition,” Cancer Discov 3:308-323 (2013); Wyce, A. et al. “BETinhibition silences expression of MYCN and BCL2 and induces cytotoxicityin neuroblastoma tumor models,” PLoS One 8:e72967 (2014)), neurofibroma,neuroma, nodular melanoma, NUT-midline carcinoma (Filippakopoulos, P.,et al., “Selective inhibition of BET bromodomains,” Nature468(7327):1067-73 (2010)), ocular cancer, oligoastrocytoma,oligodendroglioma, oncocytoma, optic nerve sheath meningioma, opticnerve tumor, oral cancer, osteosarcoma (Lamoureux, F. et al. “Selectiveinhibition of BET bromodomain epigenetic signalling interferes with thebone-associated tumour vicious cycle” Nat Commun 5:3511 (2014); Lee, D.H. et al. “Synergistic effect of JQ1 and rapamycin for treatment ofhuman osteosarcoma,” Int J Cancer 136(9):2055-2064 (2014)), ovariancancer, Pancoast tumor, papillary thyroid cancer, paraganglioma,pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitarytumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma,primary central nervous system lymphoma, primary effusion lymphoma(Tolani, B. et al. “Targeting Myc in KSHV-associated primary effusionlymphoma with BET bromodomain inhibitors,” Oncogene 33:2928-2937(2014)), primary peritoneal cancer, prostate cancer (Asangani, I. A. etal. “Therapeutic targeting of BET bromodomain proteins incastration-resistant prostate cancer,” Nature 510:278-282 (2014); Cho,H. et al. “RapidCaP, a novel GEM model for metastatic prostate canceranalysis and therapy, reveals myc as a driver of Pten-mutantmetastasis,” Cancer Discov 4:318-333 (2014); Gao, L. et al. “Androgenreceptor promotes ligand-independent prostate cancer progression throughc-Myc upregulation,” PLoS One 8:e63563 (2013): Wyce, A. et al.“Inhibition of BET bromodomain proteins as a therapeutic approach inprostate cancer,” Oncotarget 4:2419-2429 (2013)), pancreatic cancer(Sahai, V. et al. “BET bromodomain inhibitors block growth of pancreaticcancer cells in three-dimensional collagen,” Mol Cancer Ther13:1907-1917 (2014)), pharyngeal cancer, pseudomyxoma peritonei, renalcell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma,rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma,Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromaltumor, signet ring cell carcinoma, skin cancer, small blue round celltumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sootwart, spinal tumor, splenic marginal zone lymphoma, squamous cellcarcinoma, synovial sarcoma, Sezary's disease, small intestine cancer,squamous carcinoma, stomach cancer, testicular cancer, thecoma, thyroidcancer, transitional cell carcinoma, throat cancer, urachal cancer,urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer,verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginalcancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms'tumor. Thus, one aspect of the inventions provides compounds,compositions, and methods for treating such cancers.

BET inhibitors of the invention may be useful in the treatment ofcancers that are resistant to current and future cancer treatments, asBET proteins are involved in the mechanisms of resistance of severalanti-cancer treatment, including chemotherapy (Feng, Q., et al. “Anepigenomic approach to therapy for tamoxifen-resistant breast cancer”Cell Res 24:809-819 (2014)), immunotherapy (Emadali, A., et al.“Identification of a novel BET bromodomain inhibitor-sensitive, generegulatory circuit that controls Rituximab response and tumour growth inaggressive lymphoid cancers,” EMBO Mol Med 5:1180-1195 (2013)).,hormone-deprivation therapies (Asangani, I. A. et al. “Therapeutictargeting of BET bromodomain proteins in castration-resistant prostatecancer,” Nature 510:278-282 (2014)), or other molecules ((Knoechel, B.et al. “An epigenetic mechanism of resistance to targeted therapy in Tcell acute lymphoblastic leukemia,” Nat Genet 46:364-370 (2014)). Inthese instances, the BET proteins are involved in the resistancemechanism to the cancer therapy, and treatment with a BET inhibitorcould either restore sensitivity to the treatment, inhibit proliferationor induce cell death or senescence, either alone or in combination withother therapies (Moros, A. et al. “Synergistic antitumor activity oflenalidomide with the BET bromodomain inhibitor CP1203 inbortezomib-resistant mantle cell lymphoma,” Leukemia 28:2049-2059(2014)).

BET inhibitors may be useful in the treatment of benign proliferativeand fibrotic disorders, including benign soft tissue tumors, bonetumors, brain and spinal tumors, eyelid and orbital tumors, granuloma,lipoma, meningioma, multiple endocrine neoplasia, nasal polyps,pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheickeratoses, stomach polyps, thyroid nodules, cystic neoplasms of thepancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castlemandisease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenicgranuloma, juvenile polyposis syndrome, idiopathic pulmonary fibrosis,renal fibrosis, post-operative stricture, keloid formation, scleroderma,and cardiac fibrosis. Tang, X. et al., “Assessment of Brd4 Inhibition inIdiopathic Pulmonary Fibrosis Lung Fibroblasts and in Vivo Models ofLung Fibrosis,” Am J Pathology 183(2):470-479 (2013). Thus, one aspectof the invention provides compounds, compositions, and methods fortreating such benign proliferative and fibrotic disorders.

Cardiovascular disease (CVD) is the leading cause of mortality andmorbidity in the United States. Roger, V. L., et al., “Heart disease andstroke statistics—2012 update: a report from the American HeartAssociation,” Circulation 125(1):e2-e220 (2012). Atherosclerosis, anunderlying cause of CVD, is a multifactorial disease characterized bydyslipidemia and inflammation. BET inhibitors are expected to beefficacious in atherosclerosis and associated conditions because ofaforementioned anti-inflammatory effects as well as ability to increasetranscription of ApoA-I, the major constituent of HDL. Mirguet, O., etal., “From ApoAI upregulation to BET family bromodomain inhibition:discovery of 1-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung,C. W., et al., “Discovery and characterization of small moleculeinhibitors of the BET family bromodomains,” J Med Chem 54(11):3827-38(2011). Accordingly, one aspect of the invention provides compounds,compositions, and methods for treating cardiovascular disease, includingbut not limited to atherosclerosis.

Up-regulation of ApoA-1 is considered to be a useful strategy intreatment of atherosclerosis and CVD. Degoma, E. M. and D. J. Rader,“Novel HDL-directed pharmacotherapeutic strategies,” Nat Rev Cardiol8(5):266-77 (2011). BET inhibitors have been shown to increase ApoA-Itranscription and protein expression. Mirguet, O., et al., “From ApoAIupregulation to BET family bromodomain inhibition: discovery ofI-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung, C. W., etal., “Discovery and characterization of small molecule inhibitors of theBET family bromodomains,” J Med Chem 54(11):3827-38 (2011). It has alsobeen shown that BET inhibitors bind directly to BET proteins and inhibittheir binding to acetylated histones at the ApoA-1 promoter, suggestingthe presence of a BET protein repression complex on the ApoA-1 promoter,which can be functionally disrupted by BET inhibitors. It follows that,BET inhibitors may be useful in the treatment of disorders of lipidmetabolism via the regulation of ApoA-I and HDL such ashypercholesterolemia, dyslipidemia, atherosclerosis (Degoma, E. M. andD. J. Rader, “Novel HDL-directed pharmacotherapeutic strategies,” NatRev Cardiol 8(5):266-77 (2011)), and Alzheimer's disease and otherneurological disorders. Elliott, D. A., et al., “Apolipoproteins in thebrain: implications for neurological and psychiatric disorders,” ClinLipidol 51(4):555-573 (2010). Thus, one aspect of the invention providescompounds, compositions, and methods for treating cardiovasculardisorders by upregulation of ApoA-1.

BET inhibitors may be useful in the prevention and treatment ofconditions associated with ischemia-reperfusion injury such as, but notlimited to, myocardial infarction, stroke, acute coronary syndromes(Prinjha, R. K., J. Witherington, and K. Lee, “Place your BETs: thetherapeutic potential of bromodomains,” Trends PharmacolSci 33(3):146-53(2012)), renal reperfusion injury, organ transplantation, coronaryartery bypass grafting, cardio-pulmonary bypass procedures,hypertension, pulmonary, renal, hepatic, gastro-intestinal, orperipheral limb embolism. Accordingly, one aspect of the inventionprovides compounds, compositions, and methods for prevention andtreatment of conditions described herein that are associated withischemia-reperfusion injury.

Obesity-associated inflammation is a hallmark of type II diabetes,insulin resistance, and other metabolic disorders. Belkina, A. C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation andcancer,” Nat Rev Cancer 12(7):465-77 (2012); Denis, G. V., “Bromodomaincoactivators in cancer, obesity, type 2 diabetes, and inflammation,”Discov Med 10(55):489-99 (2010). Consistent with the ability of BETinhibitors to inhibit inflammation, gene disruption of Brd2 in miceablates inflammation and protects animals from obesity-induced insulinresistance. Wang, F., et al., “Brd2 disruption in mice causes severeobesity without Type 2 diabetes,” Biochem J 425(1):71-83 (2010). It hasbeen shown that Brd2 interacts with PPARγ and opposes itstranscriptional function. Knockdown of Brd2 in vitro promotestranscription of PPARγ-regulated networks, including those controllingadipogenesis. Denis, G. V., et al, “An emerging role forbromodomain-containing proteins in chromatin regulation andtranscriptional control of adipogenesis,” FEBS Lett 584(15):3260-8(2010). In addition Brd2 is highly expressed in pancreatic β-cells andregulates proliferation and insulin transcription. Wang, F., et al.,“Brd2 disruption in mice causes severe obesity without Type 2 diabetes,”Biochem J 425(1):71-83 (2010). Taken together, the combined effects ofBET inhibitors on inflammation and metabolism decrease insulinresistance and may be useful in the treatment of pre-diabetic and typeII diabetic individuals as well as patients with other metaboliccomplications. Belkina, A. C. and G. V. Denis, “BET domain co-regulatorsin obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77(2012). Accordingly, one aspect of the invention provides compounds,compositions, and methods for treatment and prevention of metabolicdisorders, including but not limited to obesity-associated inflammation,type II diabetes, and insulin resistance.

BET inhibitors may be useful in the prevention and treatment ofepisome-based DNA viruses including, but not limited to, humanpapillomavirus, herpes virus, Epstein-Barr virus, human immunodeficiencyvirus (Belkina, A. C. and G. V. Denis, “BET domain co-regulators inobesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012)),adenovirus, poxvirus, hepatitis B virus, and hepatitis C virus.Host-encoded BET proteins have been shown to be important fortranscriptional activation and repression of viral promoters. Brd4interacts with the E2 protein of human papilloma virus (HPV) to enableE2 mediated transcription of E2-target genes. Gagnon, D., et al.,“Proteasomal degradation of the papillomavirus E2 protein is inhibitedby overexpression of bromodomain-containing protein 4,” J Virol83(9):4127-39 (2009). Similarly, Brd2, Brd3, and Brd4 all bind to latentnuclear antigen 1 (LANAI), encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), promoting LANA1-dependent proliferation of KSHV-infectedcells. You, J., et al., “Kaposi's sarcoma-associated herpesviruslatency-associated nuclear antigen interacts with bromodomain proteinBrd4 on host mitotic chromosomes,” J Virol 80(18):8909-19 (2006). A BETinhibitor has been shown to inhibit the Brd4-mediated recruitment of thetranscription elongation complex pTEFb to the Epstein-Barr virus (EBV)viral C promoter, suggesting therapeutic value for EBV-associatedmalignancies. Palermo, R. D., et al., “RNA polymerase II stallingpromotes nucleosome occlusion and pTEFb recruitment to driveimmortalization by Epstein-Barr virus,” PLoS Pathog 7(10):e1002334(2011). Also, a BET inhibitor reactivated HIV in models of latent T cellinfection and latent monocyte infection, potentially allowing for viraleradication by complementary anti-retroviral therapy. Zhu, J., et al.,“Reactivation of Latent HIV-1 by Inhibition of BRD4,” Cell Rep2(4):807-816 (2012); Banerjee, C., et al., “BET bromodomain inhibitionas a novel strategy for reactivation of HIV-1,” J Leukoc Biol92(6):1147-1154 (2012); Bartholomeeusen, K., et al., “BET bromodomaininhibition activates transcription via a transient release of P-TEFbfrom 7SK snRNP,” J Biol Chem 287(43):36609-36616 (2012); Li, Z., et al.,“The BET bromodomain inhibitor JQ1 activates HIV latency throughantagonizing Brd4 inhibition of Tat-transactivation,” Nucleic Acids Res(2012). Thus, the invention also provides compounds, compositions, andmethods for treatment and prevention of episome-based DNA virusinfections. In particular, one aspect of the invention providescompounds, compositions, and methods for treatment and/or prevention ofa viral infection, including, but not limited to infection by HPV, KSHV,EBV, HIV, HBV, HCV, adenovirus, poxvirus herpes virus, or a malignancyassociated with that infection.

Some central nervous system (CNS) diseases are characterized bydisorders in epigenetic processes. Brd2 haplo-insufficiency has beenlinked to neuronal deficits and epilepsy. Velisek, L., et al.,“GABAergic neuron deficit as an idiopathic generalized epilepsymechanism: the role of BRD2 haploinsufficiency in juvenile myoclonicepilepsy,” PLoS One 6(8): e23656 (2011). SNPs in variousbromodomain-containing proteins have also been linked to mentaldisorders including schizophrenia and bipolar disorders. Prinjha, R. K.,J. Witherington, and K. Lee, “Place your BETs: the therapeutic potentialof bromodomains,” Trends Pharmacol Sci 33(3):146-53 (2012). In addition,the ability of BET inhibitors to increase ApoA-I transcription may makeBET inhibitors useful in Alzheimer's disease therapy considering thesuggested relationship between increased ApoA-I and Alzheimer's diseaseand other neurological disorders. Elliott, D. A., et al.,“Apolipoproteins in the brain: implications for neurological andpsychiatric disorders,” Clin Lipidol 51(4):555-573 (2010). Accordingly,one aspect of the invention provides compounds, compositions, andmethods for treating such CNS diseases and disorders.

BRDT is the testis-specific member of the BET protein family which isessential for chromatin remodeling during spermatogenesis. Gaucher, J.,et al., “Bromodomain-dependent stage-specific male genome programming byBrdt,” EMBO J 31(19):3809-20 (2012); Shang, E., et al., “The firstbromodomain of Brdt, a testis-specific member of the BET sub-family ofdouble-bromodomain-containing proteins, is essential for male germ celldifferentiation,” Development 134(19):3507-15 (2007). Genetic depletionof BRDT or inhibition of BRDT interaction with acetylated histones by aBET inhibitor resulted in a contraceptive effect in mice, which wasreversible when small molecule BET inhibitors were used. Matzuk, M. M.,et al., “Small-Molecule Inhibition of BRDT for Male Contraception,” Cell150(4):673-684 (2012); Berkovits, B. D., et al., “The testis-specificdouble bromodomain-containing protein BRDT forms a complex with multiplespliceosome components and is required for mRNA splicing and 3′-UTRtruncation in round spermatids,” Nucleic Acids Res 40(15):7162-75(2012). These data suggest potential utility of BET inhibitors as anovel and efficacious approach to male contraception. Thus, anotheraspect of the invention provides compounds, compositions, and methodsfor male contraception.

Monocyte chemotactic protein-1 (MCP-1, CCL2) plays an important role incardiovascular disease. Niu, J. and P. E. Kolattukudy, “Role of MCP-1 incardiovascular disease: molecular mechanisms and clinical implications,”Clin Sci (Lond) 117(3):95-109 (2009). MCP-1, by its chemotacticactivity, regulates recruitment of monocytes from the arterial lumen tothe subendothelial space, where they develop into macrophage foam cells,and initiate the formation of fatty streaks which can develop intoatherosclerotic plaque. Dawson, J., et al., “Targeting monocytechemoattractant protein-1 signalling in disease,” Expert Opin TherTargets 7(1):35-48 (2003). The critical role of MCP-1 (and its cognatereceptor CCR2) in the development of atherosclerosis has been examinedin various transgenic and knockout mouse models on a hyperlipidemicbackground. Boring, L., et al., “Decreased lesion formation in CCR2−/−mice reveals a role for chemokines in the initiation ofatherosclerosis,” Nature 394(6696):894-7 (1998); Gosling, J., et al.,“MCP-1 deficiency reduces susceptibility to atherosclerosis in mice thatoverexpress human apolipoprotein B,” J Clin Invest 103(6):773-8 (1999);Gu, L., et al., “Absence of monocyte chemoattractant protein-1 reducesatherosclerosis in low density lipoprotein receptor-deficient mice,” MolCell 2(2):275-81 (1998); Aiello, R. J., et al., “Monocytechemoattractant protein-1 accelerates atherosclerosis in apolipoproteinE-deficient mice,” Arterioscler Thromb Vasc Biol 19(6):1518-25 (1999).These reports demonstrate that abrogation of MCP-1 signaling results indecreased macrophage infiltration to the arterial wall and decreasedatherosclerotic lesion development.

The association between MCP-1 and cardiovascular disease in humans iswell-established. Niu, J. and P. E. Kolattukudy, “Role of MCP-1 incardiovascular disease: molecular mechanisms and clinical implications,”Clin Sci (Lond) 117(3):95-109 (2009). MCP-1 and its receptor areoverexpressed by endothelial cells, smooth muscle cells, andinfiltrating monocytes/macrophages in human atherosclerotic plaque.Nelken, N. A., et al., “Monocyte chemoattractant protein-1 in humanatheromatous plaques,” J Clin Invest 88(4):1121-7 (1991). Moreover,elevated circulating levels of MCP-1 are positively correlated with mostcardiovascular risk factors, measures of coronary atherosclerosisburden, and the incidence of coronary heart disease (CHD). Deo, R., etal., “Association among plasma levels of monocyte chemoattractantprotein-1, traditional cardiovascular risk factors, and subclinicalatherosclerosis,” J Am Coll Cardiol 44(9):1812-8 (2004). CHD patientswith among the highest levels of MCP-1 are those with acute coronarysyndrome (ACS). de Lemos, J. A., et al., “Association between plasmalevels of monocyte chemoattractant protein-1 and long-term clinicaloutcomes in patients with acute coronary syndromes,” Circulation107(5):690-5 (2003). In addition to playing a role in the underlyinginflammation associated with CHD, MCP-1 has been shown to be involved inplaque rupture, ischemic/reperfusion injury, restenosis, and hearttransplant rejection. Niu, J. and P. E. Kolattukudy, “Role of MCP-1 incardiovascular disease: molecular mechanisms and clinical implications,”Clin Sci (Lond) 117(3):95-109 (2009).

MCP-1 also promotes tissue inflammation associated with autoimmunediseases including rheumatoid arthritis (RA) and multiple sclerosis(MS). MCP-1 plays a role in the infiltration of macrophages andlymphocytes into the joint in RA, and is overexpressed in the synovialfluid of RA patients. Koch, A. E., et al., “Enhanced production ofmonocyte chemoattractant protein-1 in rheumatoid arthritis,” J ClinInvest 90(3):772-9 (1992). Blockade of MCP-1 and MCP-1 signaling inanimal models of RA have also shown the importance of MCP-1 tomacrophage accumulation and proinflammatory cytokine expressionassociated with RA. Brodmerkel, C. M., et al., “Discovery andpharmacological characterization of a novel rodent-active CCR2antagonist, INCB3344,” J Immunol 175(8):5370-8 (2005); Bruhl, H., etal., “Dual role of CCR2 during initiation and progression ofcollagen-induced arthritis: evidence for regulatory activity of CCR2+ Tcells,” J Immunol 172(2):890-8 (2004); Gong, J. H., et al., “Anantagonist of monocyte chemoattractant protein 1 (MCP-1) inhibitsarthritis in the MRL-lpr mouse model,” J Exp Med 186(1):131-7 (1997);65. Gong, J. H., et al., “Post-onset inhibition of murine arthritisusing combined chemokine antagonist therapy,” Rheumatology (Oxford43(1): 39-42 (2004).

Overexpression of MCP-1, in the brain, cerebrospinal fluid (CSF), andblood, has also been associated with chronic and acute MS in humans.Mahad, D. J. and R. M. Ransohoff, “The role of MCP-1 (CCL2) and CCR2 inmultiple sclerosis and experimental autoimmune encephalomyelitis (EAE),”Semin Immunol 15(1):23-32 (2003). MCP-1 is overexpressed by a variety ofcell types in the brain during disease progression and contributes tothe infiltration of macrophages and lymphocytes which mediate the tissuedamage associated with MS. Genetic depletion of MCP-1 or CCR2 in theexperimental autoimmune encephalomyelitis (EAE) mouse model, a modelresembling human MS, results in resistance to disease, primarily becauseof decreased macrophage infiltration to the CNS. Fife, B. T., et al.,“CC chemokine receptor 2 is critical for induction of experimentalautoimmune encephalomyelitis,” J Exp Med 192(6):899-905 (2000); Huang,D. R., et al., “Absence of monocyte chemoattractant protein 1 in miceleads to decreased local macrophage recruitment and antigen-specific Thelper cell type 1 immune response in experimental autoimmuneencephalomyelitis,” J Exp Med 193(6):713-26 (2001).

Preclinical data have suggested that small- and large-moleculeinhibitors of MCP-1 and CCR2 have potential as therapeutic agents ininflammatory and autoimmune indications. Thus, one aspect of theinvention provides compounds, compositions, and methods for treatingcardiovascular, inflammatory, and autoimmune conditions associated withMCP-1 and CCR2.

Accordingly, the invention provides compounds that are useful forinhibition of BET protein function by binding to bromodomains,pharmaceutical compositions comprising one or more of those compounds,and use of these compounds or compositions in the treatment andprevention of diseases and conditions, including, but not limited to,cancer, autoimmune, and cardiovascular diseases.

One embodiment of the invention provides compounds of Formula I andmethods of administering a therapeutically effective amount of thosecompounds to a mammal (e.g., a human) in need thereof:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

-   -   X is selected from CH and N;    -   Y is selected from —NH, —NR_(1b) and oxygen;    -   Z is selected from N, and —CH—;    -   R_(1a) and R_(1b) are independently selected from alkyl (C₁-C₆),        carbocycle (C₃-C₁₀), heterocycle (C₂-C₁₀) optionally substituted        with 1 to 3 groups selected from R₄;    -   R₂ is selected from aryl (C₅-C₁₀) and heteroaryl (C₅-C₁₀)        optionally substituted with 1 to 5 groups selected from R₅;    -   R₃ is selected from carbocycle (C₃-C₁₀) and heterocycle (C₂-C₁₀)        optionally substituted with 1 to 5 groups selected from R₅;    -   each R₄ is independently selected from deuterium, alkyl (C₁-C₆)        (such as methyl, ethyl, propyl, isopropyl, butyl), cycloalkyl        (C₃-C₈) (such as cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl); alkoxy (C₁-C₆) (such as methoxy, ethoxy,        isopropoxy), amino (such as —NH₂, —NHMe, —NHEt, —NHiPr,        —NHBu-NMe₂, NMeEt, —NEt₂, —NEtBu), —NHC(O)NH-alkyl(C₁-C₆),        halogen (such as F, Cl), amide (such as —NHC(O)Me, —NHC(O)Et,        —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, —CN, —N₃, ketone (such        as acetyl, —C(O)Et, —C(O)Pr), —S(O)-alkyl(C₁-C₄) (such as        —S(O)Me, —S(O)Et), —SO₂-alkyl(C₁-C₆) (such as —SO₂Me, —SO₂Et,        —SO₂Pr), thioalkyl(C₁-C₆) (such as —SMe, —SEt, —SPr, —SBu),        —COOH, and ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each of        which may be optionally substituted with hydrogen, F, Cl, Br,        —OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo; and each R₅        is independently selected from deuterium, alkyl (C₁-C₆) (such as        methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C₁-C₆) (such        as methoxy, ethoxy, isopropoxy), amino (such as —NH₂, —NHMe,        —NHEt, —NHiPr, —NHBu-NMe₂, NMeEt, —NEt₂, —NEtBu), —NHC(O)NH—        alkyl(C₁-C₆), halogen (such as F, Cl), amide (such as —NHC(O)Me,        —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, —CN, —N₃,        ketone (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)-alkyl(C₁-C₄)        (such as —S(O)Me, —S(O)Et), —SO₂-alkyl(C₁-C₆) (such as —SO₂Me,        —SO₂Et, —SO₂Pr), thioalkyl(C₁-C₆) (such as —SMe, —SEt, —SPr,        —SBu), —COOH, and ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu),        each of which may be optionally substituted with hydrogen, F,        Cl, Br, —OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-OXO.

In another aspect of the invention, a pharmaceutical compositioncomprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable carriers,diluents or excipients is provided.

In yet another aspect of the invention there is provided a compound ofFormula I, or a pharmaceutically acceptable salt thereof for use intherapy, in particular in the treatment of diseases or conditions forwhich a bromodomain inhibitor is indicated.

In yet another aspect of the invention there is provided a compound ofFormula I, or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of diseases or conditionsfor which a bromodomain inhibitor is indicated.

Definitions

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout.

As used herein, “cardiovascular disease” refers to diseases, disordersand conditions of the heart and circulatory system that are mediated byBET inhibition. Exemplary cardiovascular diseases, includingcholesterol- or lipid-related disorders, include, but are not limitedto, acute coronary syndrome, angina, arteriosclerosis, atherosclerosis,carotid atherosclerosis, cerebrovascular disease, cerebral infarction,congestive heart failure, congenital heart disease, coronary heartdisease, coronary artery disease, coronary plaque stabilization,dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familialhypercholesterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, and lipoprotein abnormalitiesassociated with Alzheimer's disease, obesity, diabetes mellitus,syndrome X, impotence, multiple sclerosis, Parkinson's disease, andinflammatory diseases.

As used herein, “inflammatory diseases” refers to diseases, disorders,and conditions that are mediated by BET inhibition. Exemplaryinflammatory diseases, include, but are not limited to, arthritis,asthma, dermatitis, psoriasis, cystic fibrosis, post transplantationlate and chronic solid organ rejection, multiple sclerosis, systemiclupus erythematosus, inflammatory bowel diseases, autoimmune diabetes,diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy,ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury,post-angioplasty restenosis, chronic obstructive pulmonary disease(COPD), glomerulonephritis, Graves disease, gastrointestinal allergies,conjunctivitis, atherosclerosis, coronary artery disease, angina, andsmall artery disease.

As used herein, “cancer” refers to diseases, disorders, and conditionsthat are mediated by BET inhibition. Exemplary cancers, include, but arenot limited to, chronic lymphocytic leukemia and multiple myeloma,follicular lymphoma, diffuse large B cell lymphoma with germinal centerphenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomasand activated, anaplastic large cell lymphoma, neuroblastoma and primaryneuroectodermal tumor, rhabdomyosarcoma, prostate cancer, breast cancer,NMC (NUT-midline carcinoma), acute myeloid leukemia (AML), acute Blymphoblastic leukemia (B-ALL), Burkitt's Lymphoma, B-cell lymphoma,melanoma, mixed lineage leukemia, multiple myeloma, pro-myelocyticleukemia (PML), non-Hodgkin's lymphoma, neuroblastoma, medulloblastoma,lung carcinoma (NSCLC, SCLC), and colon carcinoma.

“Subject” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation, or experiment. The methodsdescribed herein may be useful for both human therapy and veterinaryapplications. In one embodiment, the subject is a human.

As used herein, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to inhibiting the progression of a disease ordisorder, either physically, e.g., stabilization of a discerniblesymptom, physiologically, e.g., stabilization of a physical parameter,or both. In yet another embodiment, “treatment” or “treating” refers todelaying the onset of a disease or disorder. For example, treating acholesterol disorder may comprise decreasing blood cholesterol levels.

As used herein, “prevention” or “preventing” refers to a reduction ofthe risk of acquiring a given disease or disorder.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which is does not. For example, “optionally substituted aryl”encompasses both “aryl” and “substituted aryl” as defined below. It willbe understood by those skilled in the art, with respect to any groupcontaining one or more substituents, that such groups are not intendedto introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

As used herein, the term “hydrate” refers to a crystal form with eithera stoichiometric or non-stoichiometric amount of water is incorporatedinto the crystal structure.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-8 carbon atoms, referred to hereinas (C₂-C₈)alkenyl. Exemplary alkenyl groups include, but are not limitedto, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and4-(2-methyl-3-butene)-pentenyl.

The term “alkoxy” as used herein refers to an alkyl group attached to anoxygen (—O-alkyl-). “Alkoxy” groups also include an alkenyl groupattached to an oxygen (“alkenyloxy”) or an alkynyl group attached to anoxygen (“alkynyloxy”) groups. Exemplary alkoxy groups include, but arenot limited to, groups with an alkyl, alkenyl or alkynyl group of 1-8carbon atoms, referred to herein as (C₁-C₈)alkoxy. Exemplary alkoxygroups include, but are not limited to methoxy and ethoxy.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-8 carbonatoms, referred to herein as (C₁-C₈)alkyl. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, andoctyl.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-8 carbon atoms, referred to hereinas (C₂-C₈)alkynyl. Exemplary alkynyl groups include, but are not limitedto, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

The term “amide” as used herein refers to the form —NR_(a)C(O)(R_(b))—or —C(O)NR_(b)R_(c), wherein R_(a), R_(b) and R_(c) are eachindependently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amidecan be attached to another group through the carbon, the nitrogen,R_(b), or R_(c). The amide also may be cyclic, for example R_(b) andR_(c), may be joined to form a 3- to 8-membered ring, such as 5- or6-membered ring. The term “amide” encompasses groups such assulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versionsthereof. The term “amide” also encompasses an amide group attached to acarboxy group, e.g., -amide-COOH or salts such as -amide-COONa, an aminogroup attached to a carboxy group (e.g., -amino-COOH or salts such as-amino-COONa).

The term “amine” or “amino” as used herein refers to the form—NR_(d)R_(e) or —N(R_(d))R_(e)—, where R_(d) and R_(e) are independentlyselected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate,cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen. The aminocan be attached to the parent molecular group through the nitrogen. Theamino also may be cyclic, for example any two of R_(d) and R_(e) may bejoined together or with the N to form a 3- to 12-membered ring (e.g.,morpholino or piperidinyl). The term amino also includes thecorresponding quaternary ammonium salt of any amino group. Exemplaryamino groups include alkylamino groups, wherein at least one of R_(d) orR_(e) is an alkyl group. In some embodiments R_(d) and R_(e) each may beoptionally substituted with hydroxyl, halogen, alkoxy, ester, or amino.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic, aromatic ring system. The aryl group can optionallybe fused to one or more rings selected from aryls, cycloalkyls, andheterocyclyls. The aryl groups of this present disclosure can besubstituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary arylgroups include, but are not limited to, phenyl, tolyl, anthracenyl,fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fusedcarbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary arylgroups also include, but are not limited to a monocyclic aromatic ringsystem, wherein the ring comprises 6 carbon atoms, referred to herein as“(C₆)aryl.”

The term “arylalkyl” as used herein refers to an alkyl group having atleast one aryl substituent (e.g., -aryl-alkyl-). Exemplary arylalkylgroups include, but are not limited to, arylalkyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylalkyl.”

The term “carbamate” as used herein refers to the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i)—, or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently selected fromalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include,but are not limited to, arylcarbamates or heteroaryl carbamates (e.g.,wherein at least one of R_(g), R_(h) and R_(i) are independentlyselected from aryl or heteroaryl, such as pyridine, pyridazine,pyrimidine, and pyrazine).

The term “carbocycle” as used herein refers to an aryl or cycloalkylgroup.

The term “carboxy” as used herein refers to —COOH or its correspondingcarboxylate salts (e.g., —COONa). The term carboxy also includes“carboxycarbonyl,” e.g. a carboxy group attached to a carbonyl group,e.g., —C(O)—COOH or salts, such as —C(O)—COONa.

The term “cyano” as used herein refers to —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to an oxygen.

The term “cycloalkyl” as used herein refers to a saturated orunsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of3-12 carbons, or 3-8 carbons, referred to herein as “(C₃-C₈)cycloalkyl,”derived from a cycloalkane. Exemplary cycloalkyl groups include, but arenot limited to, cyclohexanes, cyclohexenes, cyclopentanes, andcyclopentenes. Cycloalkyl groups may be substituted with alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Cycloalkyl groups can be fused to other cycloalkyl saturated orunsaturated, aryl, or heterocyclyl groups.

The term “dicarboxylic acid” as used herein refers to a group containingat least two carboxylic acid groups such as saturated and unsaturatedhydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylicacids include alkyl dicarboxylic acids. Dicarboxylic acids may besubstituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether,formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include,but are not limited to succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid,aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(−)-malicacid, (+)/(−) tartaric acid, isophthalic acid, and terephthalic acid.Dicarboxylic acids further include carboxylic acid derivatives thereof,such as anhydrides, imides, hydrazides (for example, succinic anhydrideand succinimide).

The term “ester” refers to the structure —C(O)O—, —C(O)O—R_(j)—,—R_(k)C(O)O—R_(j)—, or —R_(k)C(O)O—, where O is not bound to hydrogen,and R_(j) and R_(k) can independently be selected from alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl,ether, haloalkyl, heteroaryl, and heterocyclyl. R_(k) can be a hydrogenatom, but R_(j) cannot be a hydrogen atom. The ester may be cyclic, forexample the carbon atom and R_(j), the oxygen atom and R_(k), or R_(j)and R_(k) may be joined to form a 3- to 12-membered ring. Exemplaryesters include, but are not limited to, alkyl esters wherein at leastone of R_(j) or R_(k) is alkyl, such as —O—C(O)-alkyl, —C(O)—O-alkyl-,and -alkyl-C(O)—O-alkyl-. Exemplary esters also include aryl orheteoraryl esters, e.g. wherein at least one of R_(j) or R_(k) is aheteroaryl group such as pyridine, pyridazine, pyrimidine and pyrazine,such as a nicotinate ester. Exemplary esters also include reverse estershaving the structure —R_(k)C(O)O—, where the oxygen is bound to theparent molecule. Exemplary reverse esters include succinate,D-argininate, L-argininate, L-lysinate and D-lysinate. Esters alsoinclude carboxylic acid anhydrides and acid halides.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The term “haloalkyl” as used herein refers to an alkyl group substitutedwith one or more halogen atoms. “Haloalkyls” also encompass alkenyl oralkynyl groups substituted with one or more halogen atoms.

The term “heteroaryl” as used herein refers to a mono-, bi-, ormulti-cyclic, aromatic ring system containing one or more heteroatoms,for example 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur.Heteroaryls can be substituted with one or more substituents includingalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Heteroaryls can also be fused to non-aromatic rings. Illustrativeexamples of heteroaryl groups include, but are not limited to,pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl,pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl,phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as“(C₂-C₅)heteroaryl.”

The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as usedherein refer to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-memberedring containing one, two, or three heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Heterocycles can be aromatic(heteroaryls) or non-aromatic. Heterocycles can be substituted with oneor more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Heterocycles also includebicyclic, tricyclic, and tetracyclic groups in which any of the aboveheterocyclic rings is fused to one or two rings independently selectedfrom aryls, cycloalkyls, and heterocycles. Exemplary heterocyclesinclude acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl,dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl,homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl,isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl,piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl,pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl,tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

The terms “hydroxy” and “hydroxyl” as used herein refer to —OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy attached toan alkyl group.

The term “hydroxyaryl” as used herein refers to a hydroxy attached to anaryl group.

The term “ketone” as used herein refers to the structure —C(O)—R_(n)(such as acetyl, —C(O)CH₃) or —R_(n)—C(O)—R_(o)—. The ketone can beattached to another group through R_(n) or R_(o). R_(n) or R_(o) can bealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R_(n) orR_(o) can be joined to form a 3- to 12-membered ring.

The term “monoester” as used herein refers to an analogue of adicarboxylic acid wherein one of the carboxylic acids is functionalizedas an ester and the other carboxylic acid is a free carboxylic acid orsalt of a carboxylic acid. Examples of monoesters include, but are notlimited to, to monoesters of succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, oxalic and maleic acid.

The term “phenyl” as used herein refers to a 6-membered carbocyclicaromatic ring. The phenyl group can also be fused to a cyclohexane orcyclopentane ring. Phenyl can be substituted with one or moresubstituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone.

The term “thioalkyl” as used herein refers to an alkyl group attached toa sulfur (—S-alkyl-).

“Alkyl,” “alkenyl,” “alkynyl”, “alkoxy”, “amino” and “amide” groups canbe optionally substituted with or interrupted by or branched with atleast one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide, thioketone, ureido and N. The substituentsmay be branched to form a substituted or unsubstituted heterocycle orcycloalkyl.

As used herein, a suitable substitution on an optionally substitutedsubstituent refers to a group that does not nullify the synthetic orpharmaceutical utility of the compounds of the present disclosure or theintermediates useful for preparing them. Examples of suitablesubstitutions include, but are not limited to: C₁₋₈ alkyl, alkenyl oralkynyl; C₁₋₆ aryl, C₂₋₅ heteroaryl; C₃₇ cycloalkyl; C₁₋₈ alkoxy; C₆aryloxy; —CN; —OH; oxo; halo, carboxy; amino, such as —NH(C₁₋₈ alkyl),—N(C₁₋₈ alkyl)₂, —NH((C₆)aryl), or —N((C₆)aryl)₂; formyl; ketones, suchas —CO(C₁₋₈ alkyl), —CO((C₆ aryl) esters, such as —CO₂(C₁₋₈ alkyl) and—CO₂ (C₆ aryl). One of skill in art can readily choose a suitablesubstitution based on the stability and pharmacological and syntheticactivity of the compound of the present disclosure.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutically acceptable composition” as used herein refersto a composition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present disclosurethat are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the presentdisclosure. A discussion is provided in Higuchi et al., “Prodrugs asNovel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentcompositions. Compounds included in the present compositions that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfate, citrate, matate, acetate, oxalate, chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentcompositions, that are acidic in nature are capable of forming basesalts with various pharmacologically acceptable cations. Examples ofsuch salts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present disclosure encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

Individual stereoisomers of compounds of the present disclosure can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Stereoisomers can also be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentdisclosure. The present disclosure encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangements of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The compounds disclosed herein may exist as tautomers and bothtautomeric forms are intended to be encompassed by the scope of thepresent disclosure, even though only one tautomeric structure isdepicted.

EXEMPLARY EMBODIMENTS OF THE INVENTION

Certain embodiments of the invention provide compounds of Formula I,which include compounds of Formula Ia, compositions and formulationscontaining such compounds, and methods of using and making suchcompounds.

Some embodiments relate to a compound according to Formula I:

-   -   or a stereoisomer, tautomer, pharmaceutically acceptable salt,        or hydrate thereof, wherein:    -   X is selected from CH and N;    -   Y is selected from —NH, —N—R_(1b) and oxygen;    -   Z is selected from N, and —CH—;    -   R_(1a) and R_(1b) are independently selected from alkyl (C₁-C₆),        carbocycle (C₃-C₁₀), and heterocycle (C₂-C₁₀) optionally        substituted with 1 to 3 groups selected from R₄;    -   R₂ is selected from aryl (C₅-C₁₀) and heteroaryl (C₅-C₁₀)        optionally substituted with 1 to 5 groups selected from R₅;    -   R₃ is selected from carbocycle (C₃-C₁₀) and heterocycle (C₂-C₁₀)        optionally substituted with 1 to 5 groups selected from R₅;    -   each R₄ is independently selected from deuterium, alkyl (C₁-C₆)        (such as methyl, ethyl, propyl, isopropyl, butyl), cycloalkyl        (C₃-C₈) (such as cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl), alkoxy (C₁-C₆) (such as methoxy, ethoxy,        isopropoxy), amino (such as —NH₂, —NHMe, —NHEt, —NHiPr,        —NHBu-NMe₂, NMeEt, —NEt₂, —NEtBu), —NHC(O)NH-alkyl(C₁-C₆),        halogen (such as F, Cl), amide (such as —NHC(O)Me, —NHC(O)Et,        —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, —CN, —N₃, ketone (such        as acetyl, —C(O)Et, —C(O)Pr), —S(O)-alkyl(C₁-C₄) (such as        —S(O)Me, —S(O)Et), —SO₂-alkyl(C₁-C₆) (such as —SO₂Me, —SO₂Et,        —SO₂Pr), thioalkyl(C₁-C₆) (such as —SMe, —SEt, —SPr, —SBu),        —COOH, and ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each of        which may be optionally substituted with hydrogen, F, Cl, Br,        —OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo; and    -   each R₅ is independently selected from deuterium, alkyl (C₁-C₆)        (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy(C₁-C₆)        (such as methoxy, ethoxy, isopropoxy), amino (such as —NH₂,        —NHMe, —NHEt, —NHiPr, —NHBu-NMe₂, NMeEt, —NEt₂, —NEtBu),        —NHC(O)NH— alkyl(C₁-C₆), halogen (such as F, Cl), amide (such as        —NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃,        —CN, —N₃, ketone (such as acetyl, —C(O)Et, —C(O)Pr),        —S(O)-alkyl(C₁-C₄) (such as —S(O)Me, —S(O)Et), —SO₂-alkyl(C₁-C₆)        (such as —SO₂Me, —SO₂Et, —SO₂Pr), thioalkyl(C₁-C₆) (such as        —SMe, —SEt, —SPr, —SBu), —COOH, and ester (such as —C(O)OMe,        —C(O)OEt, —C(O)OBu), each of which may be optionally substituted        with hydrogen, F, Cl, Br, —OH, —NH₂, —NHMe, —OMe, —SMe, oxo,        and/or thio-OXO.

Some embodiments provide compound of Formula Ia, which are a subset ofcompounds of Formula I, compositions and formulations containing suchcompounds, and methods of using and making such compounds:

-   -   or a stereoisomer, tautomer, pharmaceutically acceptable salt,        or hydrate thereof, wherein: R_(1a) is selected from alkyl        (C₁-C₆), carbocycle (C₃-C₁₀), and heterocycle (C₂-C₁₀)        optionally substituted with 1 to 3 groups selected from R₄;    -   R₂ is selected from aryl (C₅-C₁₀) and heteroaryl (C₅-C₁₀)        optionally substituted with 1 to 5 groups selected from R₅;    -   R₃ is selected from carbocycle (C₃-C₁₀) and heterocycle (C₂-C₁₀)        optionally substituted with 1 to 5 groups selected from R₅;    -   each R₄ is independently selected from deuterium, alkyl (C₁-C₆)        (such as methyl, ethyl, propyl, isopropyl, butyl), cycloalkyl        (C₃-C₈) (such as cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl), alkoxy (C₁-C₆) (such as methoxy, ethoxy,        isopropoxy), amino (such as —NH₂, —NHMe, —NHEt, —NHiPr,        —NHBu-NMe₂, NMeEt, —NEt₂, —NEtBu), —NHC(O)NH-alkyl(C₁-C₆),        halogen (such as F, Cl), amide (such as —NHC(O)Me, —NHC(O)Et,        —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, —CN, —N₃, ketone (such        as acetyl, —C(O)Et, —C(O)Pr), —S(O)-alkyl(C₁-C₄) (such as        —S(O)Me, —S(O)Et), —SO₂-alkyl(C₁-C₆) (such as —SO₂Me, —SO₂Et,        —SO₂Pr), thioalkyl(C₁-C₆) (such as —SMe, —SEt, —SPr, —SBu),        —COOH, and ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each of        which may be optionally substituted with hydrogen, F, Cl, Br,        —OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo; and each R₅        is independently selected from deuterium, alkyl (C₁-C₆) (such as        methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C₁-C₆) (such        as methoxy, ethoxy, isopropoxy), amino (such as —NH₂, —NHMe,        —NHEt, —NHiPr, —NHBu-NMe₂, NMeEt, —NEt₂, —NEtBu), —NHC(O)NH—        alkyl(C₁-C₆), halogen (such as F, Cl), amide (such as —NHC(O)Me,        —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, —CN, —N₃,        ketone (C₁-C₆) (such as acetyl, —C(O)Et, —C(O)Pr),        —S(O)-alkyl(C₁-C₄) (such as —S(O)Me, —S(O)Et), —SO₂-alkyl(C₁-C₆)        (such as —SO₂Me, —SO₂Et, —SO₂Pr), thioalkyl(C₁-C₆) (such as        —SMe, —SEt, —SPr, —SBu), —COOH, and ester (such as —C(O)OMe,        —C(O)OEt, —C(O)OBu), each of which may be optionally substituted        with hydrogen, F, Cl, Br, —OH, —NH₂, —NHMe, —OMe, —SMe, oxo,        and/or thio-OXO.

In some embodiments, each R₄ in Formula I or Formula Ia is independentlyselected from deuterium, alkyl (C₁-C₆) (such as methyl, ethyl, propyl,isopropyl, butyl), alkoxy (C₁-C₆) (such as methoxy, ethoxy, isopropoxy),amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu-NMe₂, NMeEt, —NEt₂,—NEtBu), —NHC(O)NH-alkyl(C₁-C₆), halogen (such as F, Cl), amide (such as—NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, —CN, —N₃,ketone (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)-alkyl(C₁-C₄) (such as—S(O)Me, —S(O)Et), —SO₂-alkyl(C₁-C₆) (such as —SO₂Me, —SO₂Et, —SO₂Pr),thioalkyl(C₁-C₆) (such as —SMe, —SEt, —SPr, —SBu), —COOH, and ester(such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each of which may be optionallysubstituted with hydrogen, F, Cl, Br, —OH, —NH₂, —NHMe, —OMe, —SMe, oxo,and/or thio-oxo; and X, Y, Z, R_(1a), R_(1b), R₂, R₃, and R₅ are asdefined in paragraphs 83 or 84.

In some embodiments according to Formula I, X is N; and Y, Z, R_(1a),R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one or combination ofparagraphs 83-124 herein.

In some embodiments according to Formula I, X is CH; and Y, Z, R_(1a),R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one or combination ofparagraphs 83-124 herein.

In some embodiments according to Formula I, Y is —NR_(1b); and X, Z,R_(1a), R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I, Y is —NH; and X, Z, R_(1a),R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one or combination ofparagraphs 83-124 herein.

In some embodiments according to Formula I, Y is oxygen; and X, Z,R_(1a), R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I, Z is N; and X, Y, R_(1a),R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one or combination ofparagraphs 83-124 herein.

In some embodiments according to Formula I, Z is CH; and X, Y, R_(1a),R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one or combination ofparagraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R_(1a) isselected from alkyl (C₁-C₆), carbocycle (C₃-C₆), heterocycle (C₂-C₅)optionally substituted with 1 to 3 groups selected from R₄; and X, Y, Z,R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one or combination ofparagraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R_(1a) isselected from alkyl (C₁-C₆) and carbocycle (C₃-C₆) optionallysubstituted with 1 to 3 groups selected from R₄; and X, Y, Z, R_(1b),R₂, R₃, R₄, and R₅ are as defined in any one or combination ofparagraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R_(1a) isselected from, but not limited to, the following structures, which maybe optionally substituted with 1 to 3 groups selected from R₄:

and X, Y, Z, R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I of Formula Ia, R_(1a) isselected from, but not limited to, the following structures, which maybe optionally substituted with 1 to 3 groups selected from R₄:

and X, Y, Z, R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R_(1a) is

which may be optionally substituted with 1 to 3 groups selected from R₄;and X, Y, Z, R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R_(1a) is

and X, Y, Z, R_(1b), R₂,

In some embodiments according to Formula I or Formula Ia, R_(1a) isselected from, but not limited to, the following structures, which maybe optionally substituted with 1 to 3 groups selected from R₄:

and X, Y, Z, R_(1b), R₂, R₃, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-156 herein.

In some embodiments according to Formula I, R_(1b) is selected fromalkyl (C₁-C₆); and X, Y, Z, R_(1a), R₂, R₃, R₄, and R₅ are as defined inany one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I, R_(1b) is selected frommethyl and ethyl; and X, Y, Z, R_(1a), R₂, R₃, R₄, and R₅ are as definedin any one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I, R_(1b) is methyl; and X, Y,Z, R_(1a), R₂, R₃, R₄, and R₅ are as defined in any one or combinationof paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₂ is selectedfrom optionally substituted bicyclic aryl and bicyclic heteroarylgroups; and X, Y, Z, R_(1a), R_(1b), R₃, R₄, and R₅ are as defined inany one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₂ is selectedfrom aryl (C₅-C₁₀) optionally substituted with 1 to 5 groups selectedfrom R₅; and X, Y, Z, R_(1a), R_(1b), R₃, R₄, and R₅ are as defined inany one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₂ is selectedfrom heteroaryl (C₅-C₁₀) optionally substituted with 1 to 5 groupsselected from R₅; and X, Y, Z, R_(1a), R_(1b), R₃, R₄, and R₅ are asdefined in any one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₂ is selectedfrom, but not limited to, the following structures, which may beoptionally substituted with 1 to 5 groups selected from R₅:

and X, Y, Z, R_(1a), R_(1b), R₃, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₂ is selectedfrom, but not limited to, the following structures, which may beoptionally substituted with 1 to 5 groups selected from R₅:

and X, Y, Z, R_(1a), R_(1b), R₃, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₂ is selectedfrom, but not limited to, the following structures:

which may be optionally substituted with 1 to 2 groups selected fromalkyl (C₁-C₆), halogen, ketone, amide, and ester; and X, Y, Z, R_(1a),R_(1b), R₃, R₄, and R₅ are as defined in any one or combination ofparagraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₂ is selectedfrom, but not limited to, the following structures:

which may be optionally substituted with 1 to 2 groups selected fromalkyl (C₁-C₆), halogen, ketone, amide, and ester; and X, Y, Z, R_(1a),R_(1b), R₃, R₄, and R₅ are as defined in any one or combination ofparagraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₂ is selectedfrom, but not limited to, the following structures:

and X, Y, Z, R_(1a), R_(1b), R₃, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₂ is

and X, Y, Z, R_(1a), R_(1b), R₃, and R₄ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₃ is selectedfrom carbocycle (C₃-C₁₀) optionally substituted with 1 to 5 groupsselected from R₅; and X, Y, Z, R_(1a), R_(1b), R₂, R₄, and R₅ are asdefined in any one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₃ is selectedfrom aryl groups (C₅-C₁₀) optionally substituted with 1 to 5 groupsselected from R₅; and X, Y, Z, R_(1a), R_(1b), R₂, R₄, and R₅ are asdefined in any one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₃ is selectedfrom heterocycle (C₂-C₁₀) optionally substituted with 1 to 5 groupsselected from R₅; and X, Y, Z, R_(1a), R_(1b), R₂, R₄, and R₅ are asdefined in any one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₃ is selectedfrom, but not limited to, the following structures, which may beoptionally substituted with 1 to 5 groups selected from R₅:

and X, Y, Z, R_(1a), R_(1b), R₂, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₃ is selectedfrom, but not limited to, the following structures, which may beoptionally substituted with 1 to 5 groups selected from R₅:

and X, Y, Z, R_(1a), R_(1b), R₂, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₃ is selectedfrom, but not limited to, the following structures:

which may be optionally substituted with alkyl (C₁-C₆); and X, Y, Z,R_(1a), R_(1b), R₂, R₄, and R₅ are as defined in any one or combinationof paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₃ is selectedfrom, but not limited to, the following structures:

and X, Y, Z, R_(1a), R_(1b), R₂, R₄, and R₅ are as defined in any one orcombination of paragraphs 83-156 herein.

In some embodiments according to Formula I or Formula Ia, R₃ is selectedfrom phenyl groups which may be optionally substituted with 1 to 5groups selected from R₅; and X, Y, Z, R_(1a), R_(1b), R₂, R₄, and R₅ areas defined in any one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, R₃ is anunsubstituted phenyl group; and X, Y, Z, R_(1a), R_(1b), R₂, R₄, and R₅are as defined in any one or combination of paragraphs 83-124 herein.

In some embodiment according to Formula I or Formula Ia, each R₄ isindependently selected from deuterium, alkyl (C₁-C₆) (such as methyl,ethyl, propyl, isopropyl, butyl), alkoxy (C₁-C₆) (such as methoxy,ethoxy, isopropoxy), amino (such as —NH₂, —NHMe, —NHEt, —NHiPr,—NHBu-NMe₂, NMeEt, —NEt₂, —NEtBu), —NHC(O)NH-alkyl(C₁-C₆), halogen (suchas F, Cl), amide (such as —NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂,—C(O)NiPr), —CF₃, —CN, —N₃, ketone (such as acetyl, —C(O)Et, —C(O)Pr),—S(O)-alkyl(C₁-C₄) (such as —S(O)Me, —S(O)Et), —SO₂-alkyl(C₁-C₆) (suchas —SO₂Me, —SO₂Et, —SO₂Pr), and thioalkyl(C₁-C₆) (such as —SMe, —SEt,—SPr, —SBu); and X, Y, Z, R_(1a), R_(1b), R₂, R₃, and R₅ are as definedin any one or combination of paragraphs 83-124 herein.

In some embodiment according to Formula I or Formula Ia, each R₄ isindependently selected from deuterium, alkyl (C₁-C₃) (such as methyl,ethyl, propyl), alkoxy (C₁-C₃) (such as methoxy, ethoxy), and halogen(such as F, Cl); and X, Y, Z, R_(1a), R_(1b), R₂, R₃, and R₅ are asdefined in any one or combination of paragraphs 83-124 herein.

In some embodiments according to Formula I or Formula Ia, each R₄ isindependently selected from cycloalkyl (C₃-C₈) (such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl); and X, Y, Z, R_(1a), R_(1b), R₂,R₃, and R₄ are as defined in any one or combination of paragraphs 83-124herein.

In some embodiment according to Formula I or Formula Ia, each R₅ isindependently selected from deuterium, alkyl (C₁-C₆) (such as methyl,ethyl, propyl, isopropyl, butyl), alkoxy (C₁-C₆) (such as methoxy,ethoxy, isopropoxy), amino (such as —NH₂, —NHMe, —NHEt, —NHiPr,—NHBu-NMe₂, NMeEt, —NEt₂, —NEtBu), —NHC(O)NH-alkyl(C₁-C₆), halogen (suchas F, Cl), amide (such as —NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂,—C(O)NiPr), —CF₃, —CN, —N₃, ketone (such as acetyl, —C(O)Et, —C(O)Pr),—S(O)-alkyl(C₁-C₄) (such as —S(O)Me, —S(O)Et), —SO₂-alkyl(C₁-C₆) (suchas —SO₂Me, —SO₂Et, —SO₂Pr), thioalkyl(C₁-C₆) (such as —SMe, —SEt, —SPr,—SBu), —COOH, and ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu); and X,Y, Z, R_(1a), R_(1b), R₂, R₃, and R₄ are as defined in any one orcombination of paragraphs 83-123 herein.

In certain embodiments, the compound of Formula I or Formula Ia isselected from:

-   3-(5-(3-Acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   Methyl    3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-4-methylbenzoate;-   3-(4-(4-Cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-N-methylbenzamide;-   3-(4-(4-Cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)benzamide;-   4-Cyclopropyl-3-(5-(3-oxo-2,3-dihydro-1H-inden-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(2-phenyl-5-(3-propionylphenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(3-Acetyl-4-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(3-Acetyl-5-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(5-acetyl-2-methyl    phenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(5-acetylpyridin-3-yl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    formate;-   4-cyclopropyl-3-(5-(1,3-dimethyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-(Cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Isopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-(tert-Butyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopentyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclobutyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclohexyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Isobutyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(1-Methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-4-neopentyl-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-1-ethyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-1-(cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-1-(2-methoxyethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(3-methylbenzo[d]isoxazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(3-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-3-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   3-(2-(1H-Indol-6-yl)-5-(1-methyl-1H-indazol-6-yl)-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   and stereoisomers, tautomers, pharmaceutically acceptable salts, or    hydrates thereof.

In certain embodiments, the compound of Formula I is4-cyclopropyl-1-methyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-oneor a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof.

In certain embodiments, the pharmaceutically acceptable salt of acompound of Formula I is selected from a hydrochloride ordihydrochloride salt.

In certain embodiments, the pharmaceutically acceptable salt of acompound of Formula I or Formula Ia is selected from:

-   3-(5-(3-acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   methyl    3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-4-methyl    benzoate hydrochloride;-   3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-N-methyl    benzamide hydrochloride;-   3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)benzamide    hydrochloride;-   4-cyclopropyl-3-(5-(3-oxo-2,3-dihydro-1H-inden-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(2-phenyl-5-(3-propionylphenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   3-(5-(3-acetyl-4-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   3-(5-(3-acetyl-5-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   3-(5-(5-acetyl-2-methylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(3-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1,3-dimethyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    dihydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-3-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    dihydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride; and-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride; and-   stereoisomers, tautomers, or hydrates thereof.

In certain embodiments, the pharmaceutically acceptable salt of acompound of Formula I is4-cyclopropyl-1-methyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride.

Another aspect of the invention provides a method for inhibition of BETprotein function by binding to bromodomains, and their use in thetreatment and prevention of diseases and conditions in a mammal (e.g., ahuman) comprising administering a therapeutically effective amount of acompound of Formula I or Formula Ia or a stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof.

In one embodiment, because of potent effects of BET inhibitors in vitroon IL-6 and IL-17 transcription, BET inhibitor compounds of Formula I orFormula Ia or a stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof may be used as therapeutics for inflammatorydisorders in which IL-6 and/or IL-17 have been implicated in disease.The following autoimmune diseases are amenable to therapeutic use of BETinhibition by administration of a compound of Formula I or Formula Ia ora stereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof because of a prominent role of IL-6 and/or IL-17: AcuteDisseminated Encephalomyelitis (T. Ishizu et al., “CSF cytokine andchemokine profiles in acute disseminated encephalomyelitis,” JNeuroimmunol 175(1-2): 52-8 (2006)), Agammaglobulinemia (M.Gonzalez-Serrano, et al.,” Increased Pro-inflammatory CytokineProduction After Lipopolysaccharide Stimulation in Patients withX-linked Agammaglobulinemia,” J Clin Immunol 32(5):967-74 (2012)),Allergic Disease (L. McKinley et al., “TH17 cells mediatesteroid-resistant airway inflammation and airway hyperresponsiveness inmice,” J Immunol 181(6):4089-97 (2008)), Ankylosing spondylitis (A.Taylan et al., “Evaluation of the T helper 17 axis in ankylosingspondylitis,” Rheumatol Int 32(8):2511-5 (2012)), Anti-GBM/Anti-TBMnephritis (Y. Ito et al., “Pathogenic significance of interleukin-6 in apatient with antiglomerular basement membrane antibody-inducedglomerulonephritis with multinucleated giant cells,” Am J Kidney Dis26(1):72-9 (1995)), Anti-phospholipid syndrome (P. Soltesz et al.,“Immunological features of primary anti-phospholipid syndrome inconnection with endothelial dysfunction,” Rheumatology (Oxford)47(11):1628-34 (2008)), Autoimmune aplastic anemia (Y. Gu et al.,“Interleukin (IL)-17 promotes macrophages to produce IL-8, IL-6 andtumour necrosis factor-alpha in aplastic anaemia,” BrJ Haematol142(1):109-14 (2008)), Autoimmune hepatitis (L. Zhao et al.,“Interleukin-17 contributes to the pathogenesis of autoimmune hepatitisthrough inducing hepatic interleukin-6 expression,” PLoS One 6(4):e18909(2011)), Autoimmune inner ear disease (B. Gloddek et al.,“Pharmacological influence on inner ear endothelial cells in relation tothe pathogenesis of sensorineural hearing loss,” Adv Otorhinolaryngol59:75-83 (2002)), Autoimmune myocarditis (T. Yamashita et al.,“IL-6-mediated Th17 differentiation through RORgammat is essential forthe initiation of experimental autoimmune myocarditis,” Cardiovasc Res91(4):640-8 (2011)), Autoimmune pancreatitis (J. Ni et al.,” Involvementof Interleukin-17A in Pancreatic Damage in Rat Experimental AcuteNecrotizing Pancreatitis,” Inflammation (2012)), Autoimmune retinopathy(S. Hohki et al., “Blockade of interleukin-6 signaling suppressesexperimental autoimmune uveoretinitis by the inhibition of inflammatoryTh17 responses,” Exp Eye Res 91(2):162-70 (2010)), Autoimmunethrombocytopenic purpura (D. Ma et al., “Profile of Th17 cytokines(IL-17, TGF-beta, IL-6) and Th1 cytokine (IFN-gamma) in patients withimmune thrombocytopenic purpura,” Ann Hematol 87(11):899-904 (2008)),Behcet's Disease (T. Yoshimura et al., “Involvement of Th17 cells andthe effect of anti-IL-6 therapy in autoimmune uveitis,” Rheumatology(Oxford) 48(4):347-54 (2009)), Bullous pemphigoid (L. D'Auria et al.,“Cytokines and bullous pemphigoid,” Eur Cytokine Netw 10(2):123-34(1999)), Castleman's Disease (H. El-Osta and R. Kurzrock, “Castleman'sdisease: from basic mechanisms to molecular therapeutics,” Oncologist16(4):497-511 (2011)), Celiac Disease (A. Lahdenpera et al.,“Up-regulation of small intestinal interleukin-17 immunity in untreatedcoeliac disease but not in potential coeliac disease or in type 1diabetes,” Clin Exp Immunol 167(2):226-34 (2012)), Churg-Strausssyndrome (A. Fujioka et al., “The analysis of mRNA expression ofcytokines from skin lesions in Churg-Strauss syndrome,” J Dermatol25(3):171-7 (1998)), Crohn's Disease (V. Holtta et al., “IL-23/IL-17immunity as a hallmark of Crohn's disease,” Inflamm Bowel Dis14(9):1175-84 (2008)), Cogan's syndrome (M. Shibuya et al., “Successfultreatment with tocilizumab in a case of Cogan's syndrome complicatedwith aortitis,” Mod Rheumatol (2012)), Dry eye syndrome (C. De Paiva etal., “IL-17 disrupts corneal barrier following desiccating stress,”Mucosal Immunol 2(3):243-53 (2009)), Essential mixed cryoglobulinemia(A. Antonelli et al., “Serum levels of proinflammatory cytokinesinterleukin-1beta, interleukin-6, and tumor necrosis factor alpha inmixed cryoglobulinemia,” Arthritis Rheum 60(12):3841-7 (2009)),Dermatomyositis (G. Chevrel et al., “Interleukin-17 increases theeffects of IL-1 beta on muscle cells: arguments for the role of T cellsin the pathogenesis of myositis,” J Neuroimmunol 137(1-2):125-33(2003)), Devic's Disease (U. Linhares et al., “The Ex Vivo Production ofIL-6 and IL-21 by CD4(+) T Cells is Directly Associated withNeurological Disability in Neuromyelitis Optica Patients,” J ClinImmunol (2012)), Encephalitis (D. Kyburz and M. Corr, “Th17 cellsgenerated in the absence of TGF-beta induce experimental allergicencephalitis upon adoptive transfer,” Expert Rev Clin Immunol 7(3):283-5(2011)), Eosinophlic esophagitis (P. Dias and G. Banerjee, “The Role ofTh17/IL-17 on Eosinophilic Inflammation,” J Autoimmun (2012)),Eosinophilic fasciitis (P. Dias and G. Banerjee, JAutoimmun (2012)),Erythema nodosum (I. Kahawita and D. Lockwood, “Towards understandingthe pathology of erythema nodosum leprosum,” Trans R Soc Trop Med Hyg102(4):329-37 (2008)), Giant cell arteritis (J. Deng et al., “Th17 andTh1 T-cell responses in giant cell arteritis,” Circulation 121(7):906-15(2010)), Glomerulonephritis (J. Ooi et al., “Review: T helper 17 cells:their role in glomerulonephritis,” Nephrology (Carlton) 15(5):513-21(2010)), Goodpasture's syndrome (Y. Ito et al., “Pathogenic significanceof interleukin-6 in a patient with antiglomerular basement membraneantibody-induced glomerulonephritis with multinucleated giant cells,” AmJ Kidney Dis 26(1):72-9 (1995)), Granulomatosis with Polyangiitis(Wegener's) (H. Nakahama et al., “Distinct responses of interleukin-6and other laboratory parameters to treatment in a patient with Wegener'sgranulomatosis,” Intern Med 32(2):189-92 (1993)), Graves' Disease (S.Kim et al., “Increased serum interleukin-17 in Graves' ophthalmopathy,”Graefes Arch Clin Exp Ophthalmol 250(10):1521-6 (2012)), Guillain-Barresyndrome (M. Lu and J. Zhu, “The role of cytokines in Guillain-Barresyndrome,” J Neurol 258(4):533-48 (2011)), Hashimoto's thyroiditis (N.Figueroa-Vega et al., “Increased circulating pro-inflammatory cytokinesand Th17 lymphocytes in Hashimoto's thyroiditis,” J Clin EndocrinolMetab 95(2):953-62 (2009)), Hemolytic anemia (L. Xu et al., “Criticalrole of Th17 cells in development of autoimmune hemolytic anemia,” ExpHematol (2012)), Henoch-Schonlein purpura (H. Jen et al., “Increasedserum interleukin-17 and peripheral Th17 cells in children with acuteHenoch-Schonlein purpura,” Pediatr Allergy Immunol 22(8):862-8 (2011)),IgA nephropathy (F. Lin et al., “Imbalance of regulatory T cells to Th17cells in IgA nephropathy,” Scand J Clin Lab Invest 72(3):221-9 (2012)),Inclusion body myositis (P. Baron et al., “Production of IL-6 by humanmyoblasts stimulated with Abeta: relevance in the pathogenesis of IBM,”Neurology 57(9):1561-5 (2001)), Type I diabetes (A. Belkina and G.Denis, Nat Rev Cancer 12(7):465-77 (2012)), Interstitial cystitis (L.Lamale et al., “Interleukin-6, histamine, and methylhistamine asdiagnostic markers for interstitial cystitis,” Urology 68(4):702-6(2006)), Kawasaki's Disease (S. Jia et al., “The T helper type17/regulatory T cell imbalance in patients with acute Kawasaki disease,”Clin Exp Immunol 162(1):131-7 (2010)), Leukocytoclastic vasculitis (Min,C. K., et al., “Cutaneous leucoclastic vasculitis (LV) followingbortezomib therapy in a myeloma patient; association withpro-inflammatory cytokines,” Eur J Haematol 76(3):265-8 (2006)), Lichenplanus (N. Rhodus et al., “Proinflammatory cytokine levels in salivabefore and after treatment of (erosive) oral lichen planus withdexamethasone,” Oral Dis 12(2):112-6 (2006)), Lupus (SLE) (M. Mok etal., “The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2cytokines and disease activity in systemic lupus erythematosus,” JRheumatol 37(10):2046-52 (2010)), Microscopic polyangitis (A. MullerKobold et al., “In vitro up-regulation of E-selectin and induction ofinterleukin-6 in endothelial cells by autoantibodies in Wegener'sgranulomatosis and microscopic polyangiitis,” Clin Exp Rheumatol17(4):433-40 (1999)), Multiple sclerosis (F. Jadidi-Niaragh and A.Mirshafiey, “Th17 cell, the new player of neuroinflammatory process inmultiple sclerosis,” Scand J Immunol 74(1):1-13 (2011)), Myastheniagravis (R. Aricha et al., “Blocking of IL-6 suppresses experimentalautoimmune myasthenia gravis,” J Autoimmun 36(2):135-41 (2011)),myositis (G. Chevrel et al., “Interleukin-17 increases the effects ofIL-1 beta on muscle cells: arguments for the role of T cells in thepathogenesis of myositis,” J Neuroimmunol 137(1-2):125-33 (2003)), Opticneuritis (S. Icoz et al., “Enhanced IL-6 production in aquaporin-4antibody positive neuromyelitis optica patients,” Int J Neurosci120(1):71-5 (2010)), Pemphigus (E. Lopez-Robles et al., “TNFalpha andIL-6 are mediators in the blistering process of pemphigus,” Int JDermatol 40(3):185-8 (2001)), POEMS syndrome (K. Kallen et al., “Newdevelopments in IL-6 dependent biology and therapy: where do we standand what are the options?” Expert Opin Investig Drugs 8(9):1327-49(1999)), Polyarteritis nodosa (T. Kawakami et al., “Serum levels ofinterleukin-6 in patients with cutaneous polyarteritis nodosa,” ActaDerm Venereol 92(3):322-3 (2012)), Primary biliary cirrhosis (K. Haradaet al., “Periductal interleukin-17 production in association withbiliary innate immunity contributes to the pathogenesis ofcholangiopathy in primary biliary cirrhosis,” Clin Exp Immunol157(2):261-70 (2009)), Psoriasis (S. Fujishima et al., “Involvement ofIL-17F via the induction of IL-6 in psoriasis,” Arch Dermatol Res302(7):499-505 (2010)), Psoriatic arthritis (S. Raychaudhuri et al.,IL-17 receptor and its functional significance in psoriatic arthritis,”Mol Cell Biochem 359(1-2):419-29 (2012)), Pyoderma gangrenosum (T.Kawakami et al., “Reduction of interleukin-6, interleukin-8, andanti-phosphatidylserine-prothrombin complex antibody by granulocyte andmonocyte adsorption apheresis in a patient with pyoderma gangrenosum andulcerative colitis,” Am J Gastroenterol 104(9):2363-4 (2009)), Relapsingpolychondritis (M. Kawai et al., “Sustained response to tocilizumab,anti-interleukin-6 receptor antibody, in two patients with refractoryrelapsing polychondritis,” Rheumatology (Oxford) 48(3):318-9 (2009)),Rheumatoid arthritis (Z. Ash and P. Emery, “The role of tocilizumab inthe management of rheumatoid arthritis,” Expert Opin Biol Ther,12(9):1277-89 (2012)), Sarcoidosis (F. Belli et al., “Cytokines assay inperipheral blood and bronchoalveolar lavage in the diagnosis and stagingof pulmonary granulomatous diseases,” Int J Immunopathol Pharmacol13(2):61-67 (2000)), Scleroderma (T. Radstake et al., “The pronouncedTh17 profile in systemic sclerosis (SSc) together with intracellularexpression of TGFbeta and IFNgamma distinguishes SSc phenotypes,” PLoSOne, 4(6): e5903 (2009)), Sjogren's syndrome (G. Katsifis et al.,“Systemic and local interleukin-17 and linked cytokines associated withSjogren's syndrome immunopathogenesis,” Am J Pathol 175(3):1167-77(2009)), Takayasu's arteritis (Y. Sun et al., “MMP-9 and IL-6 arepotential biomarkers for disease activity in Takayasu's arteritis,” IntJ Cardiol 156(2):236-8 (2012)), Transverse myelitis (J. Graber et al.,“Interleukin-17 in transverse myelitis and multiple sclerosis,” JNeuroimmunol 196(1-2):124-32 (2008)), Ulcerative colitis (J. Mudter andM. Neurath, “11-6 signaling in inflammatory bowel disease:pathophysiological role and clinical relevance,” Inflamm Bowel Dis13(8):1016-23 (2007)), Uveitis (H. Haruta et al., “Blockade ofinterleukin-6 signaling suppresses not only th17 but alsointerphotoreceptor retinoid binding protein-specific Th1 by promotingregulatory T cells in experimental autoimmune uveoretinitis,” InvestOphthalmol Vis Sci 52(6):3264-71 (2011)), and Vitiligo (D. Bassiouny andO. Shaker, “Role of interleukin-17 in the pathogenesis of vitiligo,”Clin Exp Dermatol 36(3):292-7 115. (2011)). Thus, the invention includescompounds of Formula I or Formula Ia, stereoisomers, tautomers,pharmaceutically acceptable salts, or hydrates thereof; pharmaceuticalcompositions comprising one or more of those compounds; and methods ofusing those compounds or compositions for treating these diseases.

Acute and chronic (non-autoimmune) inflammatory diseases characterizedby increased expression of pro-inflammatory cytokines, including IL-6,MCP-1, and IL-17, would also be amenable to therapeutic BET inhibition.These include, but are not limited to, sinusitis (D. Bradley and S.Kountakis, “Role of interleukins and transforming growth factor-beta inchronic rhinosinusitis and nasal polyposis,” Laryngoscope 115(4):684-6(2005)), pneumonitis (Besnard, A. G., et al., “Inflammasome-IL-1-Th17response in allergic lung inflammation” J Mol Cell Biol 4(1):3-10(2012)), osteomyelitis (T. Yoshii et al., “Local levels ofinterleukin-1beta, -4, -6 and tumor necrosis factor alpha in anexperimental model of murine osteomyelitis due to staphylococcusaureus,” Cytokine 19(2):59-65 2002), gastritis (T. Bayraktaroglu et al.,“Serum levels of tumor necrosis factor-alpha, interleukin-6 andinterleukin-8 are not increased in dyspeptic patients with Helicobacterpylori-associated gastritis,” Mediators Inflamm 13(1):25-8 (2004)),enteritis (K. Mitsuyama et al., “STAT3 activation via interleukin 6trans-signalling contributes to ileitis in SAMP1/Yit mice,” Gut55(9):1263-9. (2006)), gingivitis (R. Johnson et al., “Interleukin-IIand IL-17 and the pathogenesis of periodontal disease,” J Periodontol75(1):37-43 (2004)), appendicitis (S. Latifi et al., “Persistentelevation of serum interleukin-6 in intraabdominal sepsis identifiesthose with prolonged length of stay,” J PediatrSurg 39(10):1548-52(2004)), irritable bowel syndrome (M. Ortiz-Lucas et al., “Irritablebowel syndrome immune hypothesis. Part two: the role of cytokines,” RevEsp Enferm Dig 102(12):711-7 (2010)), tissue graft rejection (L. Kappelet al., “IL-17 contributes to CD4-mediated graft-versus-host disease,”Blood 113(4):945-52 (2009)), chronic obstructive pulmonary disease(COPD) (S. Traves and L. Donnelly, “Th17 cells in airway diseases,” CurrMol Med 8(5):416-26 (2008)), septic shock (toxic shock syndrome, SIRS,bacterial sepsis, etc) (E. Nicodeme et al., Nature 468(7327):1119-23(2010)), osteoarthritis (L. Chen et al., “IL-17RA aptamer-mediatedrepression of IL-6 inhibits synovium inflammation in a murine model ofosteoarthritis,” Osteoarthritis Cartilage 19(6):711-8 (2011)), acutegout (W. Urano et al., “The inflammatory process in the mechanism ofdecreased serum uric acid concentrations during acute gouty arthritis,”J Rheumatol 29(9):1950-3 (2002)), acute lung injury (S. Traves and L.Donnelly, “Th17 cells in airway diseases,” Curr Mol Med 8(5):416-26(2008)), acute renal failure (E. Simmons et al., “Plasma cytokine levelspredict mortality in patients with acute renal failure,” Kidney Int65(4):1357-65 (2004)), burns (P. Paquet and G. Pierard, “Interleukin-6and the skin,” Int Arch Allergy Immunol 109(4):308-17 (1996)),Herxheimer reaction (G. Kaplanski et al., “Jarisch-Herxheimer reactioncomplicating the treatment of chronic Q fever endocarditis: elevatedTNFalpha and IL-6 serum levels,” J Infect 37(1):83-4 (1998)), and SIRSassociated with viral infections (A. Belkinaand G. Denis, Nat Rev Cancer12(7):465-77 (2012)). Thus, the invention includes compounds of FormulaI or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptablesalts, or hydrates thereof; pharmaceutical compositions comprising oneor more of those compounds; and methods of using those compounds orcompositions for treating these diseases.

In one embodiment, BET inhibitor compounds of Formula I or Formula Ia,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used for treating rheumatoid arthritis (RA) and multiple sclerosis(MS). Strong proprietary data exist for the utility of BET inhibitors inpreclinical models of RA and MS. R. Jahagirdar et al., “An OrallyBioavailable Small Molecule RVX-297 Significantly Decreases Disease in aMouse Model of Multiple Sclerosis,” World Congress of Inflammation,Paris, France (2011). Both RA and MS are characterized by adysregulation of the IL-6 and IL-17 inflammatory pathways (A. Kimura andT. Kishimoto, “IL-6: regulator of Treg/Th17 balance,” Eur J Immunol40(7):1830-5 (2010)) and thus would be especially sensitive to BETinhibition. In another embodiment, BET inhibitor compounds of Formula Ior Formula Ia, stereoisomers, tautomers, pharmaceutically acceptablesalts, or hydrates thereof may be used for treating sepsis andassociated afflictions. BET inhibition has been shown to inhibitdevelopment of sepsis, in part, by inhibiting IL-6 expression, inpreclinical models in both published (E. Nicodeme et al., Nature468(7327):1119-23 (2010)) and proprietary data.

In one embodiment, BET inhibitor compounds of Formula I or Formula Ia,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used to treat cancer. Cancers that have an overexpression,translocation, amplification, or rearrangement c-myc or other myc familyoncoproteins (MYCN, L-myc) are particularly sensitive to BET inhibition.J. Delmore et al., Cell 146(6):904-17 (2010); J. Mertz et al., Proc NatlAcad Sci USA 108(40):16669-74 (2011). These cancers include, but are notlimited to, B-acute lymphocytic leukemia, Burkitt's lymphoma, Diffuselarge cell lymphoma, Multiple myeloma, Primary plasma cell leukemia,Atypical carcinoid lung cancer, Bladder cancer, Breast cancer, Cervixcancer, Colon cancer, Gastric cancer, Glioblastoma, Hepatocellularcarcinoma, Large cell neuroendocrine carcinoma, Medulloblastoma,Melanoma, nodular, Melanoma, superficial spreading, Neuroblastoma,esophageal squamous cell carcinoma, Osteosarcoma, Ovarian cancer,Prostate cancer, Renal clear cell carcinoma, Retinoblastoma,Rhabdomyosarcoma, and Small cell lung carcinoma. M. Vita and M.Henriksson, Semin Cancer Biol 16(4):318-30 (2006).

In one embodiment, BET inhibitor compounds of Formula I or Formula Ia,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used to treat cancers that result from an aberrant regulation(overexpression, translocation, etc) of BET proteins. These include, butare not limited to, NUT midline carcinoma (Brd3 or Brd4 translocation tonutlin 1 gene) (C. French Cancer Genet Cytogenet 203(1):16-20 (2010)),B-cell lymphoma (Brd2 overexpression) (R. Greenwald et al., Blood103(4):1475-84 (2004)), non-small cell lung cancer (BrdT overexpression)(C. Grunwald et al., “Expression of multiple epigenetically regulatedcancer/germline genes in nonsmall cell lung cancer,” Int J Cancer118(10):2522-8 (2006)), esophageal cancer and head and neck squamouscell carcinoma (BrdT overexpression) (M. Scanlan et al., “Expression ofcancer-testis antigens in lung cancer: definition of bromodomaintestis-specific gene (BRDT) as a new CT gene, CT9,” Cancer Lett150(2):55-64 (2000)), and colon cancer (Brd4) (R. Rodriguez et al.,“Aberrant epigenetic regulation of bromodomain BRD4 in human coloncancer,” J Mol Med (Berl) 90(5):587-95 (2012)).

In one embodiment, because BET inhibitors decrease Brd-dependentrecruitment of pTEFb to genes involved in cell proliferation, BETinhibitor compounds of Formula I or Formula Ia, stereoisomers,tautomers, pharmaceutically acceptable salts, or hydrates thereof, orcompositions comprising one or more of those compounds may be used totreat cancers that rely on pTEFb (Cdk9/cyclin T) and BET proteins toregulate oncogenes. These cancers include, but are not limited to,chronic lymphocytic leukemia and multiple myeloma (W. Tong et al.,“Phase I and pharmacologic study of SNS-032, a potent and selectiveCdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocyticleukemia and multiple myeloma,” J Clin Oncol 28(18):3015-22 (2010)),follicular lymphoma, diffuse large B cell lymphoma with germinal centerphenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomasand activated, anaplastic large cell lymphoma (C. Bellan et al.,“CDK9/CYCLIN T1 expression during normal lymphoid differentiation andmalignant transformation,” J Pathol 203(4):946-52 (2004)), neuroblastomaand primary neuroectodermal tumor (G. De Falco et al., “Cdk9 regulatesneural differentiation and its expression correlates with thedifferentiation grade of neuroblastoma and PNET tumors,” Cancer BiolTher 4(3):277-81 (2005)), rhabdomyosarcoma (C. Simone and A. Giordano,“Abrogation of signal-dependent activation of the cdk9/cyclin T2acomplex in human RD rhabdomyosarcoma cells,” Cell Death Differ14(1):192-5 (2007)), prostate cancer (D. Lee et al., “Androgen receptorinteracts with the positive elongation factor P-TEFb and enhances theefficiency of transcriptional elongation,” J Biol Chem 276(13):9978-84(2001)), and breast cancer (K. Bartholomeeusen et al., “BET bromodomaininhibition activates transcription via a transient release of P-TEFbfrom 7SK snRNP,” J Biol Chem (2012)).

In one embodiment, BET inhibitor compounds of Formula I or Formula Ia,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used to treat cancers in which BET-responsive genes, such as CDK6,Bcl2, TYRO3, MYB, and hTERT are up-regulated. M. Dawson et al., Nature478(7370):529-33 (2011); J. Delmore et al., Cell 146(6):904-17 (2010).These cancers include, but are not limited to, pancreatic cancer, breastcancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cellprolymphocytic leukemia, malignant glioma, bladder cancer,medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barret'sadenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia,chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-celllymphoma, small cell lung cancer, and renal carcinoma. M. Ruden and N.Puri, “Novel anticancer therapeutics targeting telomerase,” Cancer TreatRev (2012); P. Kelly and A. Strasser, “The role of Bcl-2 and itspro-survival relatives in tumourigenesis and cancer therapy” Cell DeathDiffer 18(9):1414-24 (2011); T. Uchida et al., “Antitumor effect ofbcl-2 antisense phosphorothioate oligodeoxynucleotides on humanrenal-cell carcinoma cells in vitro and in mice,” Mol Urol 5(2):71-8(2001).

Published and proprietary data have shown direct effects of BETinhibition on cell proliferation in various cancers. In one embodiment,BET inhibitor compounds of Formula I or Formula Ia, stereoisomers,tautomers, pharmaceutically acceptable salts, or hydrates thereof, orcompositions comprising one or more of those compounds may be used totreat cancers for which exist published and, for some, proprietary, invivo and/or in vitro data showing a direct effect of BET inhibition oncell proliferation. These cancers include NMC (NUT-midline carcinoma),acute myeloid leukemia (AML), acute B lymphoblastic leukemia (B-ALL),Burkitt's Lymphoma, B-cell Lymphoma, Melanoma, mixed lineage leukemia,multiple myeloma, pro-myelocytic leukemia (PML), and non-Hodgkin'slymphoma. P. Filippakopoulos et al., Nature 468(7327):1067-73 (2010); M.Dawson et al., Nature 478(7370):529-33 (2011); Zuber, J., et al., “RNAiscreen identifies Brd4 as a therapeutic target in acute myeloidleukaemia,” Nature 478(7370):524-8 (2011); M. Segura, et al, CancerResearch. 72(8): Supplement 1 (2012). The compounds of the inventionhave a demonstrated BET inhibition effect on cell proliferation in vitrofor the following cancers: Neuroblastoma, Medulloblastoma, lungcarcinoma (NSCLC, SCLC), and colon carcinoma.

In one embodiment, because of potential synergy or additive effectsbetween BET inhibitors and other cancer therapy, BET inhibitor compoundsof Formula I or Formula Ia, stereoisomers, tautomers, pharmaceuticallyacceptable salts, or hydrates thereof, or compositions comprising one ormore of those compounds may be combined with other therapies,chemotherapeutic agents, or anti-proliferative agents to treat humancancer and other proliferative disorders. The list of therapeutic agentswhich can be combined with BET inhibitors in cancer treatment includes,but is not limited to, ABT-737, Azacitidine (Vidaza), AZD1152(Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235,Bleomycin Sulfate, Bortezomib (Velcade), Busulfan (Myleran),Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine(Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone,Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol(Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin,Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran),Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone),Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib),Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid(Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248(Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine(Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).

In one embodiment, BET inhibitor compounds of Formula I or Formula Ia,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used to treat benign proliferative and fibrotic disorders, includingbenign soft tissue tumors, bone tumors, brain and spinal tumors, eyelidand orbital tumors, granuloma, lipoma, meningioma, multiple endocrineneoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumorcerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cysticneoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, andcysts, Castleman disease, chronic pilonidal disease, dermatofibroma,pilar cyst, pyogenic granuloma, juvenile polyposis syndrome, idiopathicpulmonary fibrosis, renal fibrosis, post-operative stricture, keloidformation, scleroderma, and cardiac fibrosis. X. Tang et al., Am JPathology in press (2013).

In one embodiment, because of their ability to up-regulate ApoA-1transcription and protein expression (O. Mirguet et al., Bioorg Med ChemLett 22(8):2963-7 (2012); C. Chung et al., J Med Chem 54(11):3827-38(2011)), BET inhibitor compounds of Formula I or Formula Ia,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used to treat cardiovascular diseases that are generally associatedwith including dyslipidemia, atherosclerosis, hypercholesterolemia, andmetabolic syndrome (A. Belkina and G. Denis, Nat Rev Cancer 12(7):465-77(2012); G. Denis Discov Med 10(55):489-99 (2010)). In anotherembodiment, BET inhibitor compounds of Formula I or Formula Ia,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, may be used to treat non-cardiovascular disease characterizedby deficits in ApoA-1, including Alzheimer's disease. D. Elliott et al.,Clin Lipidol 51(4):555-573 (2010).

In one embodiment, BET inhibitor compounds of Formula I or Formula Ia,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used in patients with insulin resistance and type II diabetes. A.Belkina and G. Denis, Nat Rev Cancer 12(7):465-77 (2012); G. DenisDiscov Med 10(55):489-99 (2010); F. Wang et al., Biochem J 425(1):71-83(2010); G. Denis et al, FEBS Lett 584(15):3260-8 (2010). Theanti-inflammatory effects of BET inhibition would have additional valuein decreasing inflammation associated with diabetes and metabolicdisease. K. Alexandraki et al., “Inflammatory process in type 2diabetes: The role of cytokines,” Ann NY Acad Sci 1084:89-117 (2006).

In one embodiment, because of their ability to down-regulate viralpromoters, BET inhibitor compounds of Formula I or Formula Ia,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used as therapeutics for cancers that are associated with virusesincluding Epstein-Barr Virus (EBV), hepatitis virus (HBV, HCV), Kaposi'ssarcoma associated virus (KSHV), human papilloma virus (HPV), Merkelcell polyomavirus, and human cytomegalovirus (CMV). D. Gagnon et al., JVirol 83(9):4127-39 (2009); J. You et al., J Virol 80(18):8909-19(2006); R. Palermo et al., “RNA polymerase II stalling promotesnucleosome occlusion and pTEFb recruitment to drive immortalization byEpstein-Barr virus,” PLoS Pathog 7(10):e1002334 (2011); E. Poreba etal., “Epigenetic mechanisms in virus-induced tumorigenesis,” ClinEpigenetics 2(2):233-47. 2011. In another embodiment, because of theirability to reactivate HIV-1 in models of latent T cell infection andlatent monocyte infection, BET inhibitors could be used in combinationwith anti-retroviral therapeutics for treating HIV. J. Zhu, et al., CellRep (2012); C. Banerjee et al., J Leukoc Biol (2012); K. Bartholomeeusenet al., J Biol Chem (2012); Z. Li et al., Nucleic Acids Res (2012.)

In one embodiment, because of the role of epigenetic processes andbromodomain-containing proteins in neurological disorders, BET inhibitorcompounds of Formula I or Formula Ia, stereoisomers, tautomers,pharmaceutically acceptable salts, or hydrates thereof, or compositionscomprising one or more of those compounds may be used to treat diseasesincluding, but not limited to, Alzheimer's disease, Parkinson's disease,Huntington disease, bipolar disorder, schizophrenia, Rubinstein-Taybisyndrome, and epilepsy. R. Prinjha et al., Trends PharmacolSci33(3):146-53 (2012); S. Muller et al., “Bromodomains as therapeutictargets,” Expert Rev Mol Med 13:e29 (2011).

In one embodiment, because of the effect of BRDT depletion or inhibitionon spermatid development, BET inhibitor compounds of Formula I orFormula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts,or hydrates thereof, or compositions comprising one or more of thosecompounds may be used as reversible, male contraceptive agents. M.Matzuk et al., “Small-Molecule Inhibition of BRDT for MaleContraception,” Cell 150(4): p. 673-684 (2012); B. Berkovits et al.,“The testis-specific double bromodomain-containing protein BRDT forms acomplex with multiple spliceosome components and is required for mRNAsplicing and 3′-UTR truncation in round spermatids,” Nucleic Acids Res40(15):7162-75 (2012).

Pharmaceutical Compositions

Pharmaceutical compositions of the present disclosure comprise at leastone compound of Formula I or Formula Ia, or tautomer, stereoisomer,pharmaceutically acceptable salt or hydrate thereof formulated togetherwith one or more pharmaceutically acceptable carriers. Theseformulations include those suitable for oral, rectal, topical, buccaland parenteral (e.g., subcutaneous, intramuscular, intradermal, orintravenous) administration. The most suitable form of administration inany given case will depend on the degree and severity of the conditionbeing treated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of a compound of the presentdisclosure as powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such formulations may be prepared by anysuitable method of pharmacy which includes the step of bringing intoassociation at least one compound of the present disclosure as theactive compound and a carrier or excipient (which may constitute one ormore accessory ingredients). The carrier must be acceptable in the senseof being compatible with the other ingredients of the formulation andmust not be deleterious to the recipient. The carrier may be a solid ora liquid, or both, and may be formulated with at least one compounddescribed herein as the active compound in a unit-dose formulation, forexample, a tablet, which may contain from about 0.05% to about 95% byweight of the at least one active compound. Other pharmacologicallyactive substances may also be present including other compounds. Theformulations of the present disclosure may be prepared by any of thewell-known techniques of pharmacy consisting essentially of admixing thecomponents.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can, for example, be prepared by, forexample, dissolving or dispersing, at least one active compound of thepresent disclosure as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. In general, suitable formulations may be prepared byuniformly and intimately admixing the at least one active compound ofthe present disclosure with a liquid or finely divided solid carrier, orboth, and then, if necessary, shaping the product. For example, a tabletmay be prepared by compressing or molding a powder or granules of atleast one compound of the present disclosure, which may be optionallycombined with one or more accessory ingredients. Compressed tablets maybe prepared by compressing, in a suitable machine, at least one compoundof the present disclosure in a free-flowing form, such as a powder orgranules, which may be optionally mixed with a binder, lubricant, inertdiluent and/or surface active/dispersing agent(s). Molded tablets may bemade by molding, in a suitable machine, where the powdered form of atleast one compound of the present disclosure is moistened with an inertliquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising at least one compound of the present disclosure in aflavored base, usually sucrose and acacia or tragacanth, and pastillescomprising the at least one compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Formulations of the present disclosure suitable for parenteraladministration comprise sterile aqueous preparations of at least onecompound of Formula I or Formula Ia or tautomer, stereoisomer,pharmaceutically acceptable salt, or hydrate thereof, which areapproximately isotonic with the blood of the intended recipient. Thesepreparations are administered intravenously, although administration mayalso be effected by means of subcutaneous, intramuscular, or intradermalinjection. Such preparations may conveniently be prepared by admixing atleast one compound described herein with water and rendering theresulting solution sterile and isotonic with the blood. Injectablecompositions according to the present disclosure may contain from about0.1 to about 5% w/w of the active compound.

Formulations suitable for rectal administration are presented asunit-dose suppositories. These may be prepared by admixing at least onecompound as described herein with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Formulations suitable for topical application to the skin may take theform of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.Carriers and excipients which may be used include Vaseline, lanoline,polyethylene glycols, alcohols, and combinations of two or more thereof.The active compound (i.e., at least one compound of Formula I or FormulaIa or tautomer, stereoisomer, pharmaceutically acceptable salt, orhydrate thereof) is generally present at a concentration of from about0.1% to about 15% w/w of the composition, for example, from about 0.5 toabout 2%.

The amount of active compound administered may be dependent on thesubject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. Forexample, a dosing schedule may involve the daily or semi-dailyadministration of the encapsulated compound at a perceived dosage ofabout 1 μg to about 1000 mg. In another embodiment, intermittentadministration, such as on a monthly or yearly basis, of a dose of theencapsulated compound may be employed. Encapsulation facilitates accessto the site of action and allows the administration of the activeingredients simultaneously, in theory producing a synergistic effect. Inaccordance with standard dosing regimens, physicians will readilydetermine optimum dosages and will be able to readily modifyadministration to achieve such dosages.

A therapeutically effective amount of a compound or compositiondisclosed herein can be measured by the therapeutic effectiveness of thecompound. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being used. In one embodiment, thetherapeutically effective amount of a disclosed compound is sufficientto establish a maximal plasma concentration. Preliminary doses as, forexample, determined according to animal tests, and the scaling ofdosages for human administration is performed according to art-acceptedpractices.

Toxicity and therapeutic efficacy can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferable.

Data obtained from the cell culture assays or animal studies can be usedin formulating a range of dosage for use in humans. Therapeuticallyeffective dosages achieved in one animal model may be converted for usein another animal, including humans, using conversion factors known inthe art (see, e.g., Freireich et al., Cancer Chemother. Reports50(4):219-244 (1966) and Table 1 for Equivalent Surface Area DosageFactors).

TABLE 1 Equivalent Surface Area Dosage Factors: To: Mouse Rat Monkey DogHuman From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) Mouse 1 ½ ¼ ⅙ 1/12Rat 2 1 ½ ¼ 1/7 Monkey 4 2 1 ⅗ ⅓ Dog 6 4 ⅗ 1 ½ Human 12 7 3 2 1

The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized.Generally, a therapeutically effective amount may vary with thesubject's age, condition, and gender, as well as the severity of themedical condition in the subject. The dosage may be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment.

In one embodiment, a compound of Formula I or Formula Ia or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, isadministered in combination with another therapeutic agent. The othertherapeutic agent can provide additive or synergistic value relative tothe administration of a compound of the present disclosure alone. Thetherapeutic agent can be, for example, a statin; a PPAR agonist, e.g., athiazolidinedione or fibrate; a niacin, a RVX, FXR or LXR agonist; abile-acid reuptake inhibitor; a cholesterol absorption inhibitor; acholesterol synthesis inhibitor; a cholesteryl ester transfer protein(CETP), an ion-exchange resin; an antioxidant; an inhibitor of AcylCoAcholesterol acyltransferase (ACAT inhibitor); a tyrophostine; asulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; anapolipoprotein E regulator; a HMG-CoA reductase inhibitor, a microsomaltriglyceride transfer protein; an LDL-lowing drug; an HDL-raising drug;an HDL enhancer; a regulator of the apolipoprotein A-IV and/orapolipoprotein genes; or any cardiovascular drug.

In another embodiment, a compound of Formula I or Formula Ia or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof, is administered in combination with one or moreanti-inflammatory agents. Anti-inflammatory agents can includeimmunosuppressants, TNF inhibitors, corticosteroids, non-steroidalanti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs(DMARDS), and the like. Exemplary anti-inflammatory agents include, forexample, prednisone; methylprenisolone (Medrol®), triamcinolone,methotrexate (Rheumatrex®, Trexall®), hydroxychloroquine (Plaquenil®),sulfasalzine (Azulfidine®), leflunomide (Arava®), etanercept (Enbrel®),infliximab (Remicade®), adalimumab (Humira®), rituximab (Rituxan®),abatacept (Orencia®), interleukin-1, anakinra (Kineret™), ibuprofen,ketoprofen, fenoprofen, naproxen, aspirin, acetominophen, indomethacin,sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac,etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamicacid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap,etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal,salsalate, olsalazine, or sulfasalazine.

LIST OF EXEMPLARY EMBODIMENTS

-   1. A compound of Formula I:

-   -   or a stereoisomer, tautomer, pharmaceutically acceptable salt,        or hydrate thereof, wherein:        -   X is selected from CH and N;        -   Y is selected from —NH, —N—R_(1b) and oxygen;        -   Z is selected from N, and —CH—;        -   R_(1a) and R_(1b) are independently selected from alkyl            (C₁-C₆), carbocycle (C₃-C₁₀), heterocycle (C₂-C₁₀)            optionally substituted with 1 to 3 groups selected from R₄;        -   R₂ is selected from aryl (C₅-C₁₀) and heteroaryl (C₅-C₁₀)            optionally substituted with 1 to 5 groups selected from R₅;        -   R₃ is selected from carbocycle (C₃-C₁₀) and heterocycle            (C₂-C₁₀) optionally substituted with 1 to 5 groups selected            from R₅;        -   each R₄ is independently selected from deuterium, alkyl            (C₁-C₆), cycloalkyl (C₃-C₈), alkoxy (C₁-C₆), amino,            —NHC(O)NH-alkyl(C₁-C₆), halogen, amide, —CF₃, —CN, —N₃,            ketone, —S(O)-alkyl(C₁-C₄), —SO₂-alkyl(C₁-C₆),            thioalkyl(C₁-C₆), —COOH, and ester, each of which may be            optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂,            —NHMe, —OMe, —SMe, oxo, and/or thio-oxo; and        -   each R₅ is independently selected from deuterium, alkyl            (C₁-C₆), alkoxy(C₁-C₆), amino, —NHC(O)NH-alkyl(C₁-C₆),            halogen, amide, —CF₃, —CN, —N₃, ketone, —S(O)-alkyl(C₁-C₄),            —SO₂-alkyl(C₁-C₆), thioalkyl(C₁-C₆), —COOH, and ester, each            of which may be optionally substituted with hydrogen, F, Cl,            Br, —OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

-   2. A compound according to embodiment 1, wherein the compound is a    compound of Formula Ia:

-   -   or a stereoisomer, tautomer, pharmaceutically acceptable salt,        or hydrate thereof, wherein:        -   R_(1a) is selected from alkyl (C₁-C₆), carbocycle (C₃-C₁₀),            heterocycle (C₂-C₁₀) optionally substituted with 1 to 3            groups selected from R₄;        -   R₂ is selected from aryl (C₅-C₁₀) and heteroaryl (C₅-C₁₀)            optionally substituted with 1 to 5 groups selected from R₅;        -   R₃ is selected from carbocycle (C₃-C₁₀) and heterocycle            (C₂-C₁₀) optionally substituted with 1 to 5 groups selected            from R₅;        -   each R₄ is independently selected from deuterium, alkyl            (C₁-C₆), cycloalkyl (C₃-C₈), alkoxy (C₁-C₆), amino,            —NHC(O)NH-alkyl(C₁-C₆), halogen, amide, —CF₃, —CN, —N₃,            ketone, —S(O)-alkyl(C₁-C₄), —SO₂-alkyl(C₁-C₆),            thioalkyl(C₁-C₆), —COOH, and ester, each of which may be            optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂,            —NHMe, —OMe, —SMe, oxo, and/or thio-oxo; and        -   each R₅ is independently selected from deuterium, alkyl            (C₁-C₆), alkoxy (C₁-C₆), amino, —NHC(O)NH-alkyl(C₁-C₆),            halogen, amide, —CF₃, —CN, —N₃, ketone (C₁-C₆),            —S(O)-alkyl(C₁-C₄), —SO₂-alkyl(C₁-C₆), thioalkyl(C₁-C₆),            —COOH, and ester, each of which may be optionally            substituted with hydrogen, F, Cl, Br, —OH, —NH₂, —NHMe,            —OMe, —SMe, oxo, and/or thio-oxo.

-   3. The compound according to embodiment 1, wherein X is N.

-   4. The compound according to embodiment 1, wherein X is CH.

-   5. The compound according to embodiment 1, wherein Y is —NR_(1b).

-   6. The compound according to embodiment 1, wherein Y is —NH.

-   7. The compound according to embodiment 1, wherein Y is oxygen.

-   8. The compound according to embodiment 1, wherein Z is N.

-   9. The compound according to embodiment 1, wherein Z is CH.

-   10. The compound according to embodiment 1 or embodiment 2, wherein    each R₄ is independently selected from deuterium, alkyl (C₁-C₆),    alkoxy (C₁-C₆), amino, —NHC(O)NH— alkyl(C₁-C₆), halogen, amide,    —CF₃, —CN, —N₃, ketone, —S(O)-alkyl(C₁-C₄), —SO₂-alkyl(C₁-C₆),    thioalkyl(C₁-C₆), —COOH, and ester, each of which may be optionally    substituted with hydrogen, F, Cl, Br, —OH, —NH₂, —NHMe, —OMe, —SMe,    oxo, and/or thio-oxo.

-   11. The compound according to any one of embodiments 1-10, wherein    R_(1a) is selected from alkyl (C₁-C₆), carbocycle (C₃-C₆), and    heterocycle (C₂-C₅) optionally substituted with 1 to 3 groups    selected from R₄.

-   12. The compound according to any one of embodiments 1-11, wherein    R_(1a) is selected from alkyl (C₁-C₆) and carbocycle (C₃-C₆)    optionally substituted with 1 to 3 groups selected from R₄.

-   13. The compound according to any one of embodiments 1-12, wherein    R_(1a) is selected from the following structures, which may be    optionally substituted with 1 to 3 groups selected from R₄:

-   14. The compound according to any one of embodiments 1-13, wherein    R_(1a) is selected from the following structures, which may be    optionally substituted with 1 to 3 groups selected from R₄:

-   15. The compound according to any one of embodiments 1-14, wherein    R_(1a) is

optionally substituted with 1 to 3 groups selected from R₄.

-   16. The compound according to any one of embodiments 1-15, wherein    R_(1a) is

-   17. The compound according to any one of embodiments 1-11, wherein    R_(1a) is selected from the following structures, which may be    optionally substituted with 1 to 3 groups selected from R₄:

-   18. The compound according to any one of embodiments 1, 3-5, and    7-17, wherein R_(1b) is alkyl (C₁-C₆).-   19. The compound according to any one of embodiments 1, 3-5, and    7-18, wherein R_(1b) is selected from methyl and ethyl.-   20. The compound according to any one of embodiments 1, 3-5, and    7-19, wherein R_(1b) is methyl.-   21. The compound according to any one of embodiments 1-20, wherein    R₂ is selected from bicyclic aryl and bicyclic heteroaryl groups    optionally substituted with 1 to 5 R₅ groups.-   22. The compound according to any one of embodiments 1-21, wherein    R₂ is selected from aryl (C₅-C₁₀) optionally substituted with 1 to 5    groups selected from R₅.-   23. The compound according to any one of embodiments 1-21, wherein    R₂ is selected from heteroaryl (C₅-C₁₀) optionally substituted with    1 to 5 groups selected from R₅.-   24. The compound according to any one of embodiments 1-23, wherein    R₂ is selected from the following structures, which may be    optionally substituted with 1 to 5 groups selected from R₅:

-   25. The compound according to any one of embodiments 1-24, wherein    R₂ is selected from the following structures, which may be    optionally substituted with 1 to 5 groups selected from R₅:

-   26. The compound according to any one of embodiments 1-25, wherein    R₂ is selected from the following:

-   -   which may be optionally substituted with 1 to 2 groups selected        from alkyl (C₁-C₆), halogen, ketone, amide, and ester.

-   27. The compound according to any one of embodiments 1-26, wherein    R₂ is selected from the following:

-   -   which may be optionally substituted with 1 to 2 groups selected        from alkyl (C₁-C₆), halogen, ketone, amide, and ester.

-   28. The compound according to any one of embodiments 1-27, wherein    R₂ is selected from the following structures, which may be    optionally substituted with 1 to 5 groups selected from R₅:

-   29. The compound according to any one of embodiments 1-21 or 23-28,    wherein R₂ is

-   30. The compound according to any one of embodiments 1-29, wherein    R₃ is selected from carbocycle (C₃-C₁₀) optionally substituted with    1 to 5 groups selected from R₅.-   31. The compound according to any one of embodiments 1-30, wherein    R₃ is selected from aryl groups (C₅-C₁₀) optionally substituted with    1 to 5 groups selected from R₅.-   32. The compound according to any one of embodiments 1-29, wherein    R₃ is selected from heterocycle (C₂-C₁₀) optionally substituted with    1 to 5 groups selected from R₅.-   33. The compound according to any one of embodiments 1-32, wherein    R₃ is selected from the following structures, which may be    optionally substituted with 1 to 5 groups selected from R₅:

-   34. The compound according to any one of embodiments 1-33, wherein    R₃ is selected from the following structures, which may be    optionally substituted with 1 to 5 groups selected from R₅:

-   35. The compound according to any one of embodiments 1-34, wherein    R₃ is selected from the following structures, which may be    optionally substituted with alkyl (C₁-C₆):

-   36. The compound according to any one of embodiments 1-35, wherein    R₃ is selected from the following structures:

-   37. The compound according to any one of embodiments 1-36, wherein    R₃ is selected from phenyl groups which may be optionally    substituted with 1 to 5 groups selected from R₅.-   38. The compound according to any one of embodiments 1-37, wherein    R₃ is an unsubstituted phenyl group.-   39. The compound according to any one of embodiments 1-38, wherein    each R₄ is independently selected from deuterium, alkyl (C₁-C₆),    alkoxy (C₁-C₆), amino, —NHC(O)NH-alkyl(C₁-C₆), halogen, amide, —CF₃,    —CN, —N₃, ketone, —S(O)-alkyl(C₁-C₄), —SO₂-alkyl(C₁-C₆), and    thioalkyl(C₁-C₆).-   40. The compound according to any one of embodiments 1-39, wherein    each R₄ is independently selected from deuterium, alkyl (C₁-C₃),    alkoxy (C₁-C₃), and halogen.-   41. The compound according to any one of embodiments 1-40, wherein    each R₅ is independently selected from deuterium, alkyl (C₁-C₆),    alkoxy (C₁-C₆), amino, —NHC(O)NH-alkyl(C₁-C₆), halogen, amide, —CF₃,    —CN, —N₃, ketone, —S(O)-alkyl(C₁-C₄), —SO₂-alkyl(C₁-C₆),    thioalkyl(C₁-C₆), —COOH, and ester.-   42. The compound according to embodiment 1 or embodiment 2, wherein    the compound of Formula I or Formula Ia is selected from:-   3-(5-(3-Acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   Methyl    3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-4-methylbenzoate;-   3-(4-(4-Cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-N-methylbenzamide;-   3-(4-(4-Cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)benzamide;-   4-Cyclopropyl-3-(5-(3-oxo-2,3-dihydro-1H-inden-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(2-phenyl-5-(3-propionylphenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(3-Acetyl-4-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(3-Acetyl-5-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(5-acetyl-2-methylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(5-acetylpyridin-3-yl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    formate;-   4-cyclopropyl-3-(5-(1,3-dimethyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-(Cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Isopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-(tert-Butyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopentyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclobutyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclohexyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Isobutyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   3-(5-(1-Methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-4-neopentyl-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-1-methyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-1-ethyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-1-(cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-1-(2-methoxyethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(3-methyl    benzo[d]isoxazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(3-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-3-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   3-(2-(1H-Indol-6-yl)-5-(1-methyl-1H-indazol-6-yl)-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;-   and stereoisomers, tautomers, pharmaceutically acceptable salts, and    hydrates thereof.-   43. The compound of embodiment 1 or embodiment 2, wherein the    compound of Formula I or Formula Ia is selected from the following:-   3-(5-(3-acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   methyl    3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-4-methyl    benzoate hydrochloride;-   3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-N-methyl    benzamide hydrochloride;-   3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)    benzamide hydrochloride;-   4-cyclopropyl-3-(5-(3-oxo-2,3-dihydro-1H-inden-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(2-phenyl-5-(3-propionylphenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   3-(5-(3-acetyl-4-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   3-(5-(3-acetyl-5-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   3-(5-(5-acetyl-2-methylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(3-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1,3-dimethyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    dihydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-3-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    dihydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride;-   4-cyclopropyl-1-methyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one    hydrochloride; and-   and stereoisomers, tautomers, and hydrates thereof.-   44. A pharmaceutical composition comprising the compound of any one    of embodiments 1-43, and a pharmaceutically acceptable carrier.-   45. method for inhibition of BET protein function comprising    administering a therapeutically effective amount of the compound of    any one of embodiments 1-43 or a pharmaceutical composition    according to embodiment 44.-   46. A method of treating an autoimmune or inflammatory disorder    associated with BET proteins comprising administering a    therapeutically effective amount of the compound of any one of    embodiments 1-43 or a pharmaceutical composition according to    embodiment 44.-   47. A method of treating an acute or chronic non-autoimmune    inflammatory disorder characterized by disregulation of IL-6 and/or    IL-17 comprising administering a therapeutically effective amount of    the compound of any one of embodiments 1-43 or a pharmaceutical    composition according to embodiment 44.-   48. A method of treating a cancer associated with overexpression,    translocation, amplification, or rearrangement of a myc family    oncoprotein that is sensitive to BET inhibition comprising    administering a therapeutically effective amount of the compound of    any one of embodiments 1-43 or a pharmaceutical composition    according to embodiment 44.-   49. A method of treating a cancer associated with overexpression,    translocation, amplification, or rearrangement of BET proteins    comprising administering a therapeutically effective amount of the    compound of any one of embodiments 1-43 or a pharmaceutical    composition according to embodiment 44.-   50. A method of treating a cancer that relies on pTEFb    (Cdk9/cyclin T) and BET proteins to regulate oncogenes comprising    administering a therapeutically effective amount of the compound of    any one of embodiments 1-43 or a pharmaceutical composition    according to embodiment 44.-   51. A method of treating a cancer associated with upregulation of    BET responsive genes CDK6, Bcl2, TYRO3, MYB, and hTERT comprising    administering a therapeutically effective amount of the compound of    any one of embodiments 1-43 or a pharmaceutical composition    according to embodiment 44.-   52. A method of treating a cancer associated with a gene regulated    by a super enhancer comprising administering a therapeutically    effective amount of the compound of any one of embodiments 1-43 or a    pharmaceutical composition according to embodiment 44.-   53. A method of treating a cancer that is sensitive to effects of    BET inhibition comprising administering a therapeutically effective    amount of the compound of any one of embodiments 1-43 or a    pharmaceutical composition according to embodiment 44.-   54. A method of treating a cancer that is resistant to treatment    with immunotherapy, hormone-deprivation therapy, and/or chemotherapy    comprising administering a therapeutically effective amount of the    compound of any one of embodiments 1-43 or a pharmaceutical    composition according to embodiment 44.-   55. The method of any one of embodiments 45-54, wherein the compound    of any one of embodiments 1-43 or a pharmaceutical composition    according to embodiment 44 is combined with other therapies,    chemotherapeutic agents or antiproliferative agents.-   56. The method of embodiment 55, wherein the therapeutic agent is    selected from ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib),    AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin    Sulfate, Bortezomib (Velcade), Busulfan (Myleran), Camptothecin,    Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C),    Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin    (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol    (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin,    Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran),    Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone),    Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib),    Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid    (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar),    SU11248 (Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin),    Vinorelbine (Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).-   57. A method of treating a benign proliferative or fibrotic    disorder, selected from the group consisting of benign soft tissue    tumors, bone tumors, brain and spinal tumors, eyelid and orbital    tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia,    nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri,    seborrheic keratoses, stomach polyps, thyroid nodules, cystic    neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps,    and cysts, Castleman disease, chronic pilonidal disease,    dermatofibroma, pilar cyst, pyogenic granuloma, juvenile polyposis    syndrome, idiopathic pulmonary fibrosis, renal fibrosis,    post-operative stricture, keloid formation, scleroderma, and cardiac    fibrosis comprising administering a therapeutically effective amount    of the compound of any one of embodiments 1-43 or a pharmaceutical    composition according to embodiment 44.-   58. A method of treating a disease or disorder that benefits from    up-regulation or ApoAI transcription and protein expression    comprising administering a therapeutically effective amount of the    compound of any one of embodiments 1-43 or a pharmaceutical    composition according to embodiment 44.-   59. A method of treating a metabolic disease or disorder comprising    administering a therapeutically effective amount of the compound of    any one of embodiments 1-43 or a pharmaceutical composition    according to embodiment 44.-   60. A method of treating a cancer associated with a virus comprising    administering a therapeutically effective amount of the compound of    any one of embodiments 1-43 or a pharmaceutical composition    according to embodiment 44.-   61. A method for treating HIV infection comprising administering a    therapeutically effective amount of the compound of any one of    embodiments 1-43 or a pharmaceutical composition according to    embodiment 44 alone or in combination with anti-retroviral    therapeutic.-   62. A method for treating a disease or disorder selected from    Alzheimer's disease, Parkinson's disease, Huntington disease,    bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, and    epilepsy comprising administering a therapeutically effective amount    of the compound of any one of embodiments 1-43 or a pharmaceutical    composition according to embodiment 44.-   63. A method of male contraception comprising administering a    therapeutically effective amount of the compound of any one of    embodiments 1-43 or a pharmaceutical composition according to    embodiment 44.-   64. The method of embodiment 46, wherein the autoimmune or    inflammatory disorder is selected from Acute Disseminated    Encephalomyelitis, Agammaglobulinemia, Allergic Disease, Ankylosing    spondylitis, Anti-GBM/Anti-TBM nephritis, Anti-phospholipid    syndrome, Autoimmune aplastic anemia, Autoimmune hepatitis,    Autoimmune inner ear disease, Autoimmune myocarditis, Autoimmune    pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic    purpura, Behcet's Disease, Bullous pemphigoid, Castleman's Disease,    Celiac Disease, Churg-Strauss syndrome, Crohn's Disease, Cogan's    syndrome, Dry eye syndrome, Essential mixed cryoglobulinemia,    Dermatomyositis, Devic's Disease, Encephalitis, Eosinophlic    esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giant cell    arteritis, Glomerulonephritis, Goodpasture's syndrome,    Granulomatosis with Polyangiitis (Wegener's), Graves' Disease,    Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia,    Henoch-Schonlein purpura, idiopathic pulmonary fibrosis, IgA    nephropathy, Inclusion body myositis, Type I diabetes, Interstitial    cystitis, Kawasaki's Disease, Leukocytoclastic vasculitis, Lichen    planus, Lupus (SLE), Microscopic polyangitis, Multiple sclerosis,    Myasthenia gravis, myositis, Optic neuritis, Pemphigus, POEMS    syndrome, Polyarteritis nodosa, Primary biliary cirrhosis,    Psoriasis, Psoriatic arthritis, Pyoderma gangrenosum, Relapsing    polychondritis, Rheumatoid arthritis, Sarcoidosis, Scleroderma,    Sjogren's syndrome, Takayasu's arteritis, Transverse myelitis,    Ulcerative colitis, Uveitis, and Vitiligo.-   65. The method of embodiment 47, wherein the acute or chronic    non-autoimmune inflammatory disorder is selected from sinusitis,    pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis,    appendicitis, irritable bowel syndrome, tissue graft rejection,    chronic obstructive pulmonary disease (COPD), septic shock,    osteoarthritis, acute gout, acute lung injury, acute renal failure,    burns, Herxheimer reaction, and SIRS associated with viral    infections.-   66. The method of embodiment 47, wherein the acute or chronic    non-autoimmune inflammatory disorder is selected from rheumatoid    arthritis (RA) and multiple sclerosis (MS).-   67. The method of embodiment 48, wherein the cancer is selected from    B-acute lymphocytic leukemia, Burkitt's lymphoma, Diffuse large cell    lymphoma, Multiple myeloma, Primary plasma cell leukemia, Atypical    carcinoid lung cancer, Bladder cancer, Breast cancer, Cervix cancer,    Colon cancer, Gastric cancer, Glioblastoma, Hepatocellular    carcinoma, Large cell neuroendocrine carcinoma, Medulloblastoma,    Melanoma, nodular, Melanoma, superficial spreading, Neuroblastoma,    esophageal squamous cell carcinoma, Osteosarcoma, Ovarian cancer,    Prostate cancer, Renal clear cell carcinoma, Retinoblastoma,    Rhabdomyosarcoma, and Small cell lung carcinoma.-   68. The method of embodiment 49, wherein the cancer is selected from    NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer,    esophageal cancer, head and neck squamous cell carcinoma, breast    cancer, prostate cancer, and colon cancer.-   69. The method of embodiment 50, wherein the cancer is selected from    chronic lymphocytic leukemia and multiple myeloma, follicular    lymphoma, diffuse large B cell lymphoma with germinal center    phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular    lymphomas and activated, anaplastic large cell lymphoma,    neuroblastoma and primary neuroectodermal tumor, rhabdomyosarcoma,    prostate cancer, and breast cancer.-   70. The method of embodiment 51, wherein the cancer is selected from    pancreatic cancer, breast cancer, colon cancer, glioblastoma,    adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant    glioma, bladder cancer, medulloblastoma, thyroid cancer, melanoma,    multiple myeloma, Barret's adenocarcinoma, hepatoma, prostate    cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia,    mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung    cancer, and renal carcinoma.-   71. The method of embodiment 52, wherein the gene is the MYC    oncogene.-   72. The method of embodiment 53, wherein the cancer is selected from    NUT-midline carcinoma (NMV), acute myeloid leukemia (AML), acute B    lymphoblastic leukemia (B-ALL), Burkitt's Lymphoma, B-cell Lymphoma,    Melanoma, mixed lineage leukemia, multiple myeloma, pro-myelocytic    leukemia (PML), non-Hodgkin's lymphoma, Neuroblastoma,    Medulloblastoma, lung carcinoma (NSCLC, SCLC), breast cancer,    prostate cancer, and colon carcinoma.-   73. The method of embodiment 53, wherein the cancer is selected from    adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral    lentiginous melanoma, acrospiroma, acute eosinophilic leukemia,    acute erythroid leukemia, acute lymphoblastic leukemia, acute    megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid    leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma,    adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose    tissue neoplasm, adrenocortical carcinoma, adult T-cell    leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related    lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma,    ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic    thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma,    angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell    acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia,    B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell    carcinoma, biliary tract cancer, bladder cancer, blastoma, bone    cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast    cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma,    cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma,    choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the    kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical    cancer, colorectal cancer, Degos disease, desmoplastic small round    cell tumor, diffuse large B-cell lymphoma, dysembryoplastic    neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine    gland neoplasm, endodermal sinus tumor, enteropathy-associated    T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma,    fibrosarcoma, follicular lymphoma, follicular thyroid cancer,    ganglioneuroma, gastrointestinal cancer, germ cell tumor,    gestational choriocarcinoma, giant cell fibroblastoma, giant cell    tumor of the bone, glial tumor, glioblastoma multiforme, glioma,    gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell    tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy    cell leukemia, hemangioblastoma, head and neck cancer,    hemangiopericytoma, hematological malignancy, hepatoblastoma,    hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's    lymphoma, invasive lobular carcinoma, intestinal cancer, kidney    cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma,    leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma,    lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic    leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia,    liver cancer, small cell lung cancer, non-small cell lung cancer,    MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral    nerve sheath tumor, malignant triton tumor, mantle cell lymphoma,    marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ    cell tumor, medullary carcinoma of the breast, medullary thyroid    cancer, medulloblastoma, melanoma, meningioma, Merkel cell cancer,    mesothelioma, metastatic urothelial carcinoma, mixed Mullerian    tumor, mixed lineage leukemia, mucinous tumor, multiple myeloma,    muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma,    myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma,    neuroblastoma, neurofibroma, neuroma, nodular melanoma, NUT-midline    carcinoma, ocular cancer, oligoastrocytoma, oligodendroglioma,    oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral    cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary    thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma,    pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma,    polyembryoma, precursor T-lymphoblastic lymphoma, primary central    nervous system lymphoma, primary effusion lymphoma, primary    peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal    cancer, pseudomyxoma peritonei, renal cell carcinoma, renal    medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma,    Richter's transformation, rectal cancer, sarcoma, Schwannomatosis,    seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet    ring cell carcinoma, skin cancer, small blue round cell tumors,    small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot    wart, spinal tumor, splenic marginal zone lymphoma, squamous cell    carcinoma, synovial sarcoma, Sezary's disease, small intestine    cancer, squamous carcinoma, stomach cancer, testicular cancer,    thecoma, thyroid cancer, transitional cell carcinoma, throat cancer,    urachal cancer, urogenital cancer, urothelial carcinoma, uveal    melanoma, uterine cancer, verrucous carcinoma, visual pathway    glioma, vulvar cancer, vaginal cancer, Waldenstrom's    macroglobulinemia, Warthin's tumor, and Wilms' tumor.-   74. The method of embodiment 58, wherein the disease is    cardiovascular disease, dyslipidemia, atheroschlerosis,    hypercholesterolemia, metabolic syndrome, and Alzheimer's disease.-   75. The method of embodiment 59, wherein the metabolic disorder is    selected from obesity-associated inflammation, type II diabetes, and    insulin resistance.-   76. The method of embodiment 60, wherein the virus is selected from    Epstein-Barr Virus (EBV), hepatitis B virus (HBV), hepatitis C virus    (HCV), Kaposi's sarcoma associated virus (KSHV), human papilloma    virus (HPV), Merkel cell polyomavirus, and human cytomegalovirus    (CMV).

EXAMPLES

General Methods.

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance spectra wereobtained on a Bruker 400 MHz spectrometer. Spectra are given in ppm (δ)and coupling constants, J values, are reported in hertz (Hz). Massspectra analyses were performed on Shimadzu 2020 Mass Spectrometer inESI or APCI mode when appropriate.

Abbreviations

DCM: dichloromethane; DMF: dimethylformamide; EtOAc: ethyl acetate; NBS:N-bromosuccinimide; MeOH: methanol; PE: petroleum ether; SEM-CI:(2-(chloromethoxy)ethyl)trimethylsilane; TEA: triethylamine; TFA:trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layerchromatography.

General Procedure A Example 1: Preparation of3-(5-(3-Acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one

A solution of compound 1 (25.0 g, 184 mmol, 1.00 eq), ethylprop-2-ynoate (18.0 g, 184 mmol, 1.0 eq) in MeOH (200 mL) was heated at65° C. for 16 h. After cooling to 25° C., MeOH was removed under reducedpressure and the residue was purified by column chromatography(PE:EtOAc=3:1) to give an oil. The oil was dissolved in phenyl ether(200 mL) and heated at 200° C. for 30 min. TLC indicated conversion to anew spot. The reaction mixture was cooled to 25° C. and poured intopetroleum ether (500 mL), extracted with 1N HCl (2×200 mL). The combinedaqueous layers were carefully diluted with sodium bicarbonate to basicpH and extracted with ethyl acetate (5×200 mL). The combined organiclayers were dried and concentrated. The residue was purified by columnchromatography (3:1 PE:EtOAc) and washed with DCM (200 mL) to afford 2(18.0 g, 83.2 mmol, 45% yield) as a yellow solid: ¹H NMR (400 MHz,CDCl₃) δ 1.30 (t, J=7.03 Hz, 3H), 4.26 (q, J=6.94 Hz, 2H), 7.36-7.54 (m,3H), 7.92-8.02 (m, 2H), 8.13 (br s, 1H).

To a solution of compound 2 (18.0 g, 83.2 mmol, 1.0 eq) in EtOH (200 mL)was added hydrazine monohydrate (16.7 g, 333 mmol, 4.0 eq) in oneportion at 25° C. The mixture was stirred at 80° C. for 16 h. TLC showedthe reaction was completed. The mixture was cooled to 25° C. andconcentrated under reduced pressure at 40° C. The residue was purifiedby silica gel chromatography (1:10 MeOH/EtOAc) to afford 3 (14.0 g, 69.2mmol, 83% yield) as a yellow solid: ¹H NMR (400 MHz, DMSO-d6) δ7.35-7.42 (m, 1H), 7.43-7.51 (m, 2H), 7.73 (s, 1H), 7.99-8.06 (m, 1H),8.97 (br s, 1H).

To a solution of compound 3 (14.0 g, 69.2 mmol, 1.0 eq) in THF (120 mL)was added a solution of isocyanatocyclopropane (28.8 g, 346 mmol, 5.0eq) in DCM (500 mL) dropwise at 25° C. The mixture was stirred at 25° C.for 2 h. The resulting yellow precipitate was filtered and washed withEtOAc (200 mL) to afford 4 (14.0 g, 49.1 mmol, 70% yield): ESI m/z286.1[M+1]+.

To a solution of compound 4 (14 g, 49.07 mmol, 1.0 eq) in H₂O (300 mL)was added NaOH (5.89 g, 147.21 mmol, 3.0 eq) in one portion at 25° C.Then the reaction mixture was heated at 100° C. After 40 h, TLC showedthe reaction was completed and the mixture was cooled to 25° C. 3N HClwas added and at pH 5-6, a crystalline solid formed. The solid wasisolated by filtration, washed with water (30 mL) and dried at 50° C. toafford 5 (8 g, 29.93 mmol, 61% yield): ¹H NMR (400 MHz, DMSO-d6) δ0.80-0.90 (m, 2H), 0.93-1.04 (m, 2H), 3.13 (dt, J=6.90, 3.33 Hz, 1H),7.42-7.61 (m, 2H), 7.91 (s, 1H), 8.10 (d, J=7.40 Hz, 2H).

To a solution of compound 5 (8.00 g, 29.9 mmol, 1.0 eq) in DMF (60 mL)was added NBS (6.39 g, 35.9 mmol, 1.2 eq) in portions at 0° C. under N₂atmosphere. The resulting mixture was stirred at 0-10° C. for 30 min.TLC showed the reaction was complete. The reaction mixture was quenchedwith water (50 mL) and the aqueous phase was extracted with ethylacetate (6×100 mL). The combined organic layers were washed with sat.sodium thiosulfate (100 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (PE/EtOAc, 50-100%) to afford 6 (5.50 g, 15.9 mmol, 53%yield) as a yellow solid: ¹H NMR (400 MHz, DMSO-d6) δ 0.62 (br s, 2H),0.78-0.87 (m, 2H), 2.97 (br s, 1H), 7.43-7.57 (m, 3H), 7.97 (d, J=7.15Hz, 2H).

Compound 6 (50 mg, 0.14 mmol, 1.0 eq), (3-acetylphenyl)boronic acid(45.9 mg, 0.280 mmol, 2.0 eq), K₂CO₃ (40 mg, 0.28 mmol, 2.0 eq) andPd(dppf)Cl₂.CH₂Cl₂ (24 mg, 0.03 mmol, 0.20 eq) in dioxane (2 mL) and H₂O(0.5 mL) was degassed with nitrogen and then heated at 90° C. for 3 hunder nitrogen atmosphere. LCMS showed the starting material wasconsumed completely. The reaction mixture was cooled to 25° C. and thesolvent was removed in vacuo. The residue was dissolved in MeOH (10 mL)and filtered. The resulting filtrate was concentrated and purified byprep-HPLC (HCl buffer) to afford3-(5-(3-acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-onehydrochloride (Example 1) (12 mg, 31.1 umol, 22% yield) as a whitesolid: ¹H NMR (400 MHz, CD₃OD) δ 0.63-0.83 (m, 4H), 2.47 (dt, J=7.15,3.33 Hz, 1H), 2.67 (s, 3H), 7.60-7.74 (m, 4H), 7.87-7.97 (m, 1H),8.03-8.17 (m, 3H), 8.37 (t, J=1.57 Hz, 1H); ESI m/z 386.2[M+1]⁺.

General Procedure B Example 17:4-(Cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one)

To a solution of compound 2 (2.00 g, 9.25 mmol, 1.00 eq) in DMF (20 mL),was added NBS (1.98 g, 11.10 mmol, 1.20 eq) in portions at 0° C. undernitrogen. The mixture was stirred at 0-10° C. for 30 min. The mixturewas diluted with water and the aqueous phase was extracted with EtOAc(3×80 mL). The combined organic fractions were washed with a solution ofsaturated sodium thiosulfate (30 mL), dried with anhydrous sodiumsulfate and concentrated under vacuum to afford 7 (1.83 g, 6.20 mmol,67% yield) as a yellow solid: ¹H NMR (400 MHz, DMSO-d6) δ 1.34 (t,J=7.16 Hz, 3H) 4.33 (q, J=6.97 Hz, 2H) 7.49 (d, J=6.41 Hz, 3H) 8.09 (d,J=6.40 Hz, 2H) 13.51-13.85 (m, 1H).

To a mixture of compound 7 (800 mg, 2.71 mmol, 1.00 eq) and(1-methylindazol-6-yl)boronic acid (477 mg, 2.71 mmol, 1.00 eq) indioxane (10 mL) was added KOAc (266.03 mg, 2.71 mmol, 1.00 eq) andPd(dppf)Cl₂ (198 mg, 271 umol, 0.10 eq) in one portion at 25° C. undernitrogen. Then the mixture was heated to 90° C. and stirred for 16 hr.The mixture was concentrated under reduced pressure and the residue wasfiltered through silica gel (0-100% EtOAc in PE). The crude product waspurified by preparative HPLC to afford 8 (480 mg, 1.39 mmol, 51% yield)as a yellow solid: ESI m/z 347.1[M+1].

To a mixture of compound 8 (450 mg, 1.30 mmol, 1.00 eq) in EtOH (5 mL)was added hydrazine hydrate (976 mg, 19.5 mmol, 15.0 eq) in one portionat 25° C. under nitrogen. Then the reaction mixture was stirred at 80°C. for 30 hours. The mixture was concentrated and the residue was takenup in EtOAc (10 mL). The suspension was stirred for 10 min and filteredto afford 9 (300 mg, 902 umol, 69% yield) as a gray solid: ¹H NMR (400MHz, DMSO-d6) δ 4.09 (s, 3H) 4.51 (br. s., 2H) 7.42-7.55 (m, 3H) 7.64(d, J=8.67 Hz, 1H) 7.76-7.84 (m, 1H) 8.07-8.23 (m, 4H) 9.15 (br. s., 1H)12.94 (br. s., 1H).

To a mixture of compound 9 (50 mg, 150 umol, 1.00 eq) in DMF (1.0 mL)was added carbonyldiimidazole (29 mg, 180 umol, 1.2 eq) in one portionat 25° C. under nitrogen. The reaction mixture was stirred at 25° C. for16 hr and was concentrated in vacuum. The residue was taken up in water(5 mL) and stirred for 15 min. The precipitate was filtered and driedunder vacuum to afford 10 (35 mg, 97 umol, 64% yield) as a gray solid:¹H NMR (400 MHz, DMSO-d6) δ 4.10 (s, 3H) 7.03 (s, 2H) 7.42-7.57 (m, 4H)7.86 (br. s., 1H) 8.11 (d, J=13.43 Hz, 4H) 13.08-13.36 (m, 1H).

Compound 10 (35 mg, 97 umol, 1.00 eq) and cyclopropylmethanamine (69 mg,976 umol, 10.0 eq) were taken up in MeOH (2.0 mL) in a microwave tube.The sealed tube was irradiated in the microwave at 90° C. for 1.5 hr.The reaction mixture was concentrated under vacuum to afford 11 (30 mg,70 umol, 72% yield) as yellow solid: ESI m/z 430.2 [M+1]+.

To a mixture of compound 11 (20 mg, 47 umol, 1.0 eq) in EtOH (1.0 mL)was added NaOH (3M, 16 uL, 1.0 eq) in one portion at 25° C. undernitrogen. The reaction mixture was stirred at 90° C. for 16 hr. 3N HClwas added to lower the pH to 5-6 which caused a precipitate to form. Thesolid was isolated by filtration and taken up in DMF (5 mL) forpurification by preparative HPLC.4-(Cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one(Example 17) (13 mg, 32 umol, 68% yield) was isolated as a white solid:¹H NMR (400 MHz, DMSO-d₆) δ 0.08-0.41 (m, 4H) 3.67 (br. s., 2H) 4.08 (s,3H) 7.33-7.49 (m, 2H) 7.51-7.57 (m, 2H) 7.80 (d, J=8.41 Hz, 1H)8.03-8.09 (m, 2H) 8.10-8.14 (m, 2H) 11.79 (br. s., 1H); ESI m/z412.1[M+1]⁺.

General Procedure C Example 23:4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one

A solution of compound 12 (18.0 g, 142.7 mmol, 1.0 eq) and hydrazinehydrate (35.7 g, 713.7 mmol, 5.0 eq) in EtOH (200 mL) was stirred at 90°C. for 15 h. After cooling to room temperature, a precipitate formed.The solid was filtered, and dried under vacuum to afford compound 13(15.0 g, 119 mmol, 83% yield) as a white crystalline solid: ¹H NMR (400MHz, DMSO-d₆) δ 4.35 (br. s., 2H) 7.61 (s, 1H) 7.72 (d, J=0.88 Hz, 1H)9.10 (br. s., 1H) 12.49 (br. s., 1H).

Carbonyldiimidazole (17.7 g, 109.4 mmol, 1.2 eq) was added to asuspension of compound 13 (11.5 g, 91.2 mmol, 1.0 eq) in DMF (110 mL) at0° C. Initially, the solution cleared, but after stirring at 15° C. for3 hr, a precipitate formed. The solid was filtered, washed with DCM (100mL) and dried under vacuum to afford compound 14 (10.4 g, 67.7 mmol, 74%yield) as an off-white solid: ESI m/z 153.0[M+1]⁺.

A clear solution of compound 14 (5.00 g, 32.87 mmol, 1.00 eq) andcyclopropanamine (9.38 g, 164.4 mmol, 5.0 eq) in MeOH (5.00 mL) wasstirred under microwave irradiation at 80° C. for 2 hr. After cooling, aprecipitate formed. The reaction mixture was concentrated and theresidue was triturated in ethyl acetate (40 mL). The solid was filteredand dried under vacuum to afford compound 15 (4.50 g, 21.5 mmol, 65%yield) as a light-yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 0.34-0.42(m, 2H) 0.52-0.61 (m, 2H) 2.42-2.49 (m, 1H) 6.49 (br. s., 1H) 7.71 (s,1H) 7.75 (s, 2H) 9.34 (br. s., 1H) 12.53 (br. s., 1H).

A clear solution of compound 15 (4.70 g, 22.5 mmol, 1.0 eq) in 2N NaOH(13 mL) was stirred under microwave irradiation at 140° C. for 4 hr. Thereaction mixture was cooled to 0° C., and conc. HCl was added to adjustthe pH to 8. The precipitate was filtered, washed with water (100 mL)and dried under vacuum to afford compound 16 (2.90 g, 14.6 mmol, 65.1%yield, 96.4% purity) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ0.75-0.90 (m, 4H) 3.01-3.09 (m, 1H) 7.64 (s, 1H) 7.80 (s, 1H) 11.52 (s,1H) 12.50 (br. s., 1H); ESI m/z 192.1 [M+1]⁺.

N-Bromosuccinimide (5.36 g, 30.1 mmol, 1.2 eq) was added in portions toa 0° C. solution of compound 16 (4.80 g, 25.1 mmol, 1.0 eq) in DMF (40mL) over 1 hr. The reaction mixture was stirred at 0° C. for 3 h. Thereaction mixture was purified by p-HPLC directly to afford compound 17(4.60 g, 12.0 mmol, 48% yield) as a white crystalline TFA salt: ¹H NMR(400 MHz, DMSO-d₆) δ 0.51-0.61 (m, 2H) 0.73-0.83 (m, 2H) 2.85-2.95 (m,1H) 7.94 (s, 1H) 11.97 (s, 1H); ESI m/z 270.0, 272.0 [M+1]⁺.

A solution of compound 17 (4.50 g, 11.7 mmol, 1.0 eq) in DMF (2 mL) wasadded dropwise to another solution of SEM-CI (5.86 g, 35.2 mmol, 3.0 eq)in THF (50 mL) at 0° C. Then the solution was stirred at 10° C. for 1 hrat which time a precipitate formed. Sodium hydride (1.88 g, 46.9 mmol,4.0 eq) was added to the mixture in portions. Initially, the reactionmixture turn red, but the color faded as it was stirred for 15 hr. Thereaction was quenched by the dropwise addition of water (10 mL) at 0° C.Additional water (100 mL) was added and the the pH was adjusted to 7with aq. HCl. The reaction mixture was extracted with ethyl acetate(2×100 mL). The combined organic fractions were washed with brine, driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby column chromatography (10-50% EA in PE) to afford compound 18 (2.90g, 5.47 mmol, 46.7% yield) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ0.00 (s, 9H) 0.02 (s, 9H) 0.63-0.78 (m, 2H) 0.78-0.94 (m, 4H) 0.94-1.02(m, 2H) 3.03-3.11 (m, 1H) 3.39-3.48 (m, 2H) 3.63-3.74 (m, 2H) 5.21 (s,2H) 5.33 (br. s., 2H) 7.68 (s, 1H); ESI m/z 532.1, 530.1 [M+1]⁺.

Compound 18 (1.50 g, 2.83 mmol, 1.0 eq), (1-methylindazol-6-yl)boronicacid (697 mg, 3.96 mmol, 1.40 eq), K₂CO₃ (782 mg, 5.66 mmol, 2.0 eq) andPd(dppf)Cl₂ (207 mg, 283 umol, 0.10 eq) were combined in a mixed solventof dioxane (20 mL) and water (5 mL). The reaction mixture was degassedwith nitrogen and then heated at 90° C. for 15 hr under nitrogenatmosphere. The reaction mixture was concentrated under reduced pressureand the residue was purified by column chromatography (0-100% EA in DCM)to afford compound 19 (1.46 g, 80% purity) as a brown oil: ESI m/z 582.3[M+1]⁺.

n-BuLi (2.5 M, 1.81 mL, 1.80 eq) was added to a solution of compound 19(1.46 g, 2.51 mmol, 1.00 eq) in THF (33 mL) at −78° C. under a nitrogenatmosphere. The resulting slurry was stirred at −78° C. for 5 min, thena solution of 1,1,1,2,2,2-hexachloroethane (832 mg, 3.51 mmol, 1.40 eq)in THF (3 mL) was added in portions. The reaction mixture was stirredfor 30 min at −78° C. as the color turned from brown to red. Thereaction was quenched by the addition of water (40 mL) at 0° C. and thereaction mixture was extracted with ethyl acetate (2×100 mL). Thecombined organic fractions were washed with brine (50 mL), concentratedand the residue was purified by column chromatography (20%-100% EA inPE) to afford compound 20 (1.05 g, 85% purity) as a red gum: ESI m/z616.2 [M+1]⁺.

Compound 20 (100 mg, 162 umol, 1.0 eq), 4-pyridylboronic acid (40 mg,325 umol, 2.0 eq), K₂CO₃ (45 mg, 325 umol, 2.0 eq) were combined in amixed solvent of dioxane (3 mL) and water (600 uL). Pd(PPh₃)₄(19 mg, 16umol, 0.10 eq) was added under nitrogen atmosphere, and then the mixturewas stirred at 95° C. for 15 h. The reaction mixture was concentratedunder reduced pressure and the residue was purified by columnchromatography (0-10% MeOH in DCM) to afford compound 21 (80 mg) as ayellow oil: ESI m/z 659.2 [M+1]+.

A solution of compound 21 (80 mg) in 6M hydrochloric acid (10 mL) washeated to 100° C. for 3 hr. The reaction mixture was concentrated andthe residue was triturated in methanol (2 mL). The solid was isolated byfiltration to give4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onedihydrochloride (Example 23) (23 mg, 58 umol, 48% yield) as a yellowsolid: ¹H NMR (300 MHz, DMSO-d₆) δ 0.59-0.74 (m, 4H) 4.09 (s, 3H) 7.34(d, J=8.67 Hz, 1H) 7.44-7.68 (m, 1H) 7.84 (d, J=8.48 Hz, 1H) 8.04-8.21(m, 2H) 8.54 (d, J=5.46 Hz, 2H) 8.94 (d, J=6.40 Hz, 2H) 11.94 (br. s.,1H); ESI m/z 399.1 [M+1]+.

General Procedure D Example 27:4-Cyclopropyl-2-methyl-5-[4-(1-methylindazol-6-yl)-2-phenyl-1H-imidazol-5-yl]-1,2,4-triazol-3-one

SEM-CI (188 mg, 1.13 mmol, 1.95 eq) was added to a solution of compound6 (200 mg, 578 umol, 1.0 eq) and TEA (146 mg, 1.44 mmol, 2.5 eq) in DMF(6 mL). The reaction mixture was purged with nitrogen and heated at 80°C. for 2 h. The yellow mixture was cooled to 25° C. and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (20-50% EA in PE) to afford 22 (161 mg) as yellow solid:ESI m/z 477.9[M+1]⁺.

Compound 22 (50 mg, 105 umol, 1.0 eq) and (1-methylindazol-6-yl)boronicacid (26.04 mg, 147.98 umol, 1.41 eq) were combined in 1,4-dioxane (2mL) and water (400 uL). K₂CO₃ (30 mg, 217 umol, 2.1 eq) and Pd(PPh₃)₄(18mg, 16 umol, 0.15 eq) were added and the mixture was purged withnitrogen. The reaction mixture was heated at 90° C. for 20 h. Theresidue was purified by prep-TLC (5% MeOH in DCM) to afford 23 (38 mg,67 umol, 64% yield) as yellow solid: ESI m/z 528.2[M+1]⁺.

Sodium hydride (4 mg, 100 umol, 1.5 eq) was added to a solution ofcompound 23 (38 mg, 67 umol, 1.0 eq) in THF (3 mL) at −10° C. and thereaction was stirred for 1 hr at −10° C. Iodomethane (610 mg, 4.30 mmol,64.1 eq) was added dropwise and the reaction mixture was purged withnitrogen. After stirring for 16 hr at 15° C., the mixture was cooled to0° C. and quenched with ice-water (15 mL). The reaction mixture wasstirred for another 0.5 h and was extracted with DCM (2×10 mL). Thecombined organic fractions were washed with brine (2×10 mL), dried withanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by prep-TLC (10% MeOH in DCM) to afford 24 (36 mg)as yellow solid: ESI m/z 542.2[M+1]⁺.

To a solution of compound 24 (20 mg, 37 umol, 1.0 eq) in DCM (10 mL) wasadded TFA (3 mL) at 14° C. The reaction mixture was heated at 40° C. for1 hr and concentrated under reduced pressure. The residue was taken upin dioxane (3 mL), then ammonium hydroxide (1.29 mg, 36.9 umol, 1.0 eq)was added dropwise. The mixture was stirred at 14° C. for 0.5 h and wasconcentrated under reduced pressure. The residue was purified bypreparative HPLC to afford4-cyclopropyl-1-methyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride (Example 27) (3 mg, 7.3 umol, 20% yield) as light yellowsolid: ¹H-NMR (DMSO-d₆, 300 MHz): δ 8.17 (d, J=7.3 Hz, 2H), 8.09 (d,J=9.2 Hz, 2H), 7.77-7.85 (m, 1H), 7.44-7.62 (m, 3H), 7.27-7.34 (m, 1H),4.08 (s, 3H), 3.39 (s, 3H), 1.12-1.27 (m, 1H), 0.63 ppm (d, J=4.5 Hz,4H); ESI m/z 412.0 [M+1]⁺.

TABLE 2 Example Compounds General Example Chemical Name StructureProcedure Characterization Yield 1 3-(5-(3-acetylphenyl)-2-phenyl-1H-imidazol-4- yl)-4-cyclopropyl-1H- 1,2,4-triazol-5(4H)-onehydrochloride

A ¹H NMR (400 MHz, CD₃OD) δ 0.63-0.83 (m, 4H), 2.47 (dt, J = 7.15, 3.33Hz, 1H), 2.67 (s, 3H), 7.60-7.74 (m, 4H), 7.87-7.97 (m, 1H), 8.03- 8.17(m, 3H), 8.37 (t, J = 1.57 Hz, 1H); ESI m/z 386.2 [M + 1]⁺. 22% 2 methyl3-(4-(4- cyclopropyl-5-oxo-4,5- dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl- 1H-imidazol-5-yl)-4- methyl benzoatehydrochloride

A ¹H NMR (400 MHz, CD₃OD) δ 0.72-0.79 (m, 2H), 0.80-0.87 (m, 2H),2.20-2.29 (m, 1H), 2.41 (s, 3H), 3.93 (s, 3H), 7.57 (d, J = 8.03 Hz,1H), 7.65- 7.74 (m, 3H), 8.06 (dd, J = 7.53, 2.01 Hz, 2H), 8.10 (dd, J =8.03, 1.76 Hz, 1H), 8.16 (d, J = 1.63 Hz, 1H); ESI m/z 416.1 [M + 1]⁺.22% 3 3-(4-(4-cyclopropyl-5- oxo-4,5-dihydro-1H- 1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5- yl)-N-methyl benzamide hydrochloride

A ¹H NMR (400 MHz, CD₃OD) δ 0.64- 0.84 (m, 4H), 2.22-2.36 (m, H), 2.97(s, 3H), 7.63-7.80 (m, 4H), 7.83- 7.89 (m, 1H), 8.00 (d, J = 7.91 Hz,1H), 8.10 (dd, J = 8.09, 1.44 Hz, 2H), 8.23 (t, J = 1.57 Hz, 1H); ESIm/z 401.1 [M + 1]⁺. 28% 4 3-(4-(4-cyclopropyl-5- oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2- phenyl-1H-imidazol-5- yl) benzamide hydrochloride

A ¹H NMR (400 MHz, CD₃OD) δ 0.65-0.82 (m, 4H), 2.24-2.36 (m, 1H), 3.33(dt, J = 3.26, 1.63 Hz, 4H), 7.63-7.82 (m, 4H), 7.85-7.95 (m, 1H),8.04-8.19 (m, 3H), 8.29 (t, J = 1.57 Hz, 1H); ESI m/z 387.1 [M + 1]⁺.22% 5 4-cyclopropyl-3-(5-(3- oxo-2,3-dihydro-1H- inden-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H- 1,2,4-triazol-5(4H)-one hydrochloride

A ¹H NMR (400 MHz, CD₃OD) δ 0.59-0.88 (m, 4H), 2.35 (dt, J = 7.03, 3.39Hz, 1H), 2.72-2.88 (m, 2H), 3.23-3.31 (m, 2H), 7.66-7.83 (m, 4H), 7.96(dd, J = 7.97, 1.82 Hz, 1H), 8.03-8.17 (m, 3H); ESI m/z 397.1 [M + 1]⁺.16% 6 4-cyclopropyl-3-(2- phenyl-5-(3- propionylphenyl)-1H-imidazol-4-yl)-1H-1,2,4- triazol-5(4H)-one hydrochloride

A ¹H NMR (400 MHz, CD₃OD) δ 0.64-0.82 (m, 4H), 1.22 (t, J = 7.15 Hz,3H), 2.50 (tt, J = 7.07, 3.65 Hz, 1H) 3.11 (q, J = 7.15 Hz, 2H), 7.58-7.70 (m, 4H), 7.90 (d, J = 7.78 Hz, 1H), 8.01- 8.15 (m, 3H), 8.35 (s,1H); ESI m/z 400 [M + 1]⁺ 63% 7 4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)- 2-phenyl-1H-imidazol-4- yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride

A ¹H NMR (400 MHz, DMSO-d₆) δ 0.61-0.70 (m, 4H) 4.10 (s, 3H) 7.30 (dd, J= 8.41, 1.13 Hz, 1H) 7.51-7.69 (m, 3H) 7.83 (d, J = 8.53 Hz, 1H) 8.07-8.20 (m, 2H) 8.26 (d, J = 6.90 Hz, 2H) 12.08 (s, 1H); ESI m/z 398.2 [M +H]⁺.  4% 8 3-(5-(3-acetyl-4- fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4- cyclopropyl-1H-1,2,4- triazol-5(4H)-onehydrochloride

A ¹H NMR (400 MHz, CD₃OD) δ 0.67-0.74 (m, 2H), 0.76-0.84 (m, 2H), 2.45(dt, J = 6.93, 3.37 Hz, 1H), 2.69 (d, J = 4.64 Hz, 3H), 7.50 (dd, J =10.67, 8.66 Hz, 1H), 7.69-7.80 (m, 4H), 7.90- 8.01 (m, 1H), 8.09 (d, J =6.78 Hz, 2H), 8.27 (dd, J = 6.71, 2.45 Hz, 1H); ESI m/z 404 [M + 1]⁺.29% 9 3-(5-(3-acetyl-5- fluorophenyl)-2-phenyl- 1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4- triazol-5(4H)-one hydrochloride

A ¹H NMR (400 MHz, DMSO-d₆) δ 0.61-0.73 (m, 4H) 2.62 (s, 3H) 2.81 (dt, J= 7.15, 3.33 Hz, 1H) 7.45-7.59 (m, 3H) 7.73 (dt, J = 9.25, 1.90 Hz, 1H)7.86-7.91 (m, 1H) 8.11- 8.19 (m, 3H) 11.98- 12.10 (m, 1H); ESI m/z 404.1[M + 1]⁺ 13% 10 4-cyclopropyl-3-(5-(1- methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4- yl)-1H-1,2,4-triazol- 5(4H)-one hydrochloride

A ¹H NMR (400 MHz, CD₃OD) δ 0.63-0.76 (m, 4H) 2.03-2.16 (m, 1H) 4.15 (s,3H) 7.67-7.86 (m, 5H) 8.08-8.15 (m, 2H) 8.19 (s, 2H); ESI m/z 398.0 [M +1]⁺ 54% 11 3-(5-(5-acetyl-2- methylphenyl)-2- phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H- 1,2,4-triazol-5(4H)-one hydrochloride

A ¹HNMR (400 MHz, DMSO-d₆) δ 0.64-0.84 (m, 4H) 2.28 (s, 3 H) 2.58 (s, 3H) 7.45-7.61 (m, 4 H) 7.90-8.00 (m, 2 H) 8.11 (d, J = 7.28 Hz, 2 H)11.73 (br. s., 1 H) ESI m/z 400.0 [M + 1]⁺ 43% 123-(5-(5-acetylpyridin-3- yl)-2-phenyl-1H- imidazol-4-yl)-4-cyclopropyl-1H-1,2,4- triazol-5(4H)-one formate

A ¹H NMR (300 MHz, DMSO-d₆) δ 0.61-0.77 (m, 1H) 2.67 (s, 3 H) 2.79-2.96(m, 1 H) 7.41- 7.59 (m, 3 H) 8.11 (d, J = 7.16 Hz, 2 H) 8.37 (br. s., 1H) 8.62 (s, 1 H) 8.96- 9.16 (m, 2 H) 11.89 (br. s., 1 H); ESI m/z 387.0[M + 1]⁺ 22% 13 4-cyclopropyl-3-(5-(3- methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4- yl)-1H-1,2,4-triazol- 5(4H)-one hydrochloride

A ¹HNMR (400 MHz, DMSO-d₆) δ 0.63 (d, J = 4.52 Hz, 4H) 2.60- 2.66 (m,1H) 7.45-7.59 (m, 5H) 8.15 (s, 1H) 8.22 (d, J = 7.40 Hz, 2H) 11.94 (br.s., 1H) 12.87 (br. s., 1H); ESI m/z 398.4 [M + 1]⁺ 35% 144-cyclopropyl-3-(5-(1- methyl-1H- benzo[d][1,2,3]triazol-6-yl)-2-phenyl-1H- imidazol-4-yl)-1H-1,2,4- triazol-5(4H)-onehydrochloride

A ¹H-NMR (DMSO-d₆, 300 MHz): δ 11.90-12.05 (m, 1H), 8.22-8.33 (m, 1H),8.11-8.21 (m, 2H), 7.99- 8.11 (m, 1H), 7.56 (t, J = 7.4 Hz, 4H), 4.34(br. s., 3H), 2.63-2.68 (m, 1H), 0.64 ppm (br. s., 4H); ESI m/z 399.1[M + 1]⁺ 31% 15 4-cyclopropyl-3-(5-(1,3- dimethyl-1H-indazol-5-yl)-2-phenyl-1H- imidazol-4-yl)-1H-1,2,4- triazol-5(4H)-onehydrochloride

A ¹H NMR (400 MHz, CD₃OD): δ 8.16-8.23 (m, 1H), 8.08-8.15 (m, 2H),7.70-7.81 (m, 3H), 7.61- 7.70 (m, 2H), 4.05 (s, 3H), 2.60 (s, 3H), 2.09-2.20 (m, 1H), 0.62-0.75 (m, 4H); ESI m/z 412.0 [M + 1]⁺ 13% 164-cyclopropyl-3-(5-(3- methylbenzo[d]isoxazol- 5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4- triazol-5(4H)-one

A ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.15 (m, 1H), 8.00-8.07 (m, 2H),7.81-7.86 (m, 1H), 7.63- 7.70 (m, 1H), 7.44-7.58 (m, 3H), 2.61 (s, 4H),0.62-0.80 (m, 4H); ESI m/z 399.1 [M + 1]⁺  2% 17 4-(cyclopropylmethyl)-3-(5-(1-methyl-1H- indazol-6-yl)-2-phenyl- 1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one

B ¹H NMR (400 MHz, DMSO-d₆) δ 0.08-0.41 (m, 4H) 3.67 (br. s., 2H) 4.08(s, 3H) 7.33-7.49 (m, 2H) 7.51-7.57 (m, 2H) 7.80 (d, J = 8.41 Hz, 1H)8.03-8.09 (m, 2H) 8.10-8.14 (m, 2H) 11.79 (br. s., 1H); ESI m/z 412.1[M + 1]⁺ 68% 18 4-isobutyl-3-(5-(1- methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4- yl)-1H-1,2,4-triazol- 5(4H)-one

B ¹H NMR (400 MHz, DMSO-d₆) δ 0.71 (d, J = 6.65 Hz, 6H) 1.87- 2.07 (m,1H) 3.66 (br. s., 2H) 4.00 (s, 3 H) 7.12 (br. s., 1H) 7.31 (br, s., 2H)7.48-7.70 (m, 2H) 7.90 (br. s., 1H) 8.02- 8.11 (m, 3H) 11.26- 11.47 (m,1H); ESI m/z 414.2 [M + 1]⁺ 44% 19 4-cyclobutyl-3-(5-(1-methyl-1H-indazol-6-yl)- 2-phenyl-1H-imidazol-4- yl)-1H-1,2,4-triazol-5(4H)-one

B ¹H NMR (400 MHz, DMSO-d₆) δ 1.40-1.62 (m, 2H) 1.83 (br. s., 2H) 2.79(br. s., 2H) 4.03 (s, 3H) 4.51 (br. s., 1H) 7.19- 7.53 (m, 4H) 7.67 (d,J = 8.16 Hz, 1H) 7.88- 8.04 (m, 2H) 8.10 (d, J = 7.40 Hz, 2H) 11.67 (br.s., 1H) 13.21 (s, 1H); ESI m/z 412.2 [M + H]⁺ 50% 20 3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl- 1H-imidazol-4-yl)-4- neopentyl-1H-1,2,4-triazol-5(4H)-one

B ¹H NMR (400 MHz, CD₃OD) δ 0.72 (s, 9H) 3.62 (br. s., 2H) 4.13 (s, 3H)7.42 (dd, J = 8.47, 1.19 Hz, 1H) 7.50 (d, J = 7.15 Hz, 1H) 7.52- 7.58(m, 2H) 7.83 (d, J = 8.53 Hz, 1H) 8.01 (s, 1H) 8.04-8.09 (m, 3H); ESIm/z 428.3 [M + 1]⁺ 17% 21 4-cyclopentyl-3-(5-(1-methyl-1H-indazol-6-yl)- 2-phenyl-1H-imidazol-4- yl)-1H-1,2,4-triazol-5(4H)-one

B ¹H NMR (400 MHz, CD₃OD) δ 1.37-1.50 (m, 2H) 1.61 (br. s., 2H) 1.72(br. s., 2H) 2.03 (dd, J = 12.86, 8.22 Hz, 2H) 4.11 (s, 3H) 4.24 (t, J =8.78 Hz, 1H) 7.32 (d, J = 8.41 Hz, 1H) 7.47- 7.59 (m, 3H) 7.80-7.89 (m,2H) 8.03-8.10 (m, 3H); ESI m/z 426 [M + 1]⁺  7% 22 4-isopropyl-3-(5-(1-methyl-1H-indazol-6-yl)- 2-phenyl-1H-imidazol-4- yl)-1H-1,2,4-triazol-5(4H)-one

B ¹H NMR (400 MHz, CD₃OD) δ 1.28 (d, J = 6.78 Hz, 6H) 4.12 (s, 3H) 4.14-4.19 (m, 1H) 7.34 (dd, J = 8.41, 1.38 Hz, 1H) 7.47-7.58 (m, 3H) 7.83 (d,J = 8.78 Hz, 1H) 7.91 (s, 1H) 8.02-8.10 (m, 3 H); ESI m/z 400.3 [M + 1]⁺10% 23 4-cyclopropyl-3-(5-(1- methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H- imidazol-4-yl)-1H-1,2,4- triazol-5(4H)-onedihydrochloride

C ¹H NMR (300 MHz, DMSO-d₆) δ 0.59-0.74 (m, 4H) 4.09 (s, 3H) 7.34 (d, J= 8.67 Hz, 1H) 7.44- 7.68 (m, 1H) 7.84 (d, J = 8.48 Hz, 1H) 8.04- 8.21(m, 2H) 8.54 (d, J = 5.46 Hz, 2H) 8.94 (d, J = 6.40 Hz, 2H) 11.94 (br.s., 1H); ESI m/z 399.1 [M + 1]⁺ 48% 24 4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)- 2-(pyridin-3-yl)-1H- imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one dihydrochloride

C ¹H NMR (400 MHz, CD₃OD) δ 0.64-0.79 (m, 4H) 2.36-2.54 (m, 1H) 4.16 (s,3H) 7.42 (dd, J = 8.41, 1.25 Hz, 1H) 7.91 (d, J = 8.28 Hz, 1H) 8.10 (s,1H) 8.13 (s, 1H) 8.31 (dd, J = 8.22, 5.83 Hz, 1H) 9.00 (d, J = 5.27 Hz,1H) 9.28 (d, J = 8.28 Hz, 1H) 9.61 (s, 1H); ESI m/z 399.2 [M + 1]⁺ 42%25 4-cyclopropyl-3-(5-(1- methyl-1H-indazol-6-yl)-2-(1-methyl-1H-pyrazol- 4-yl)-1H-imidazol-4-yl)- 1H-1,2,4-triazol-5(4H)-one hydrochloride

C ¹H NMR (400 MHz, CD₃OD) δ 0.63-0.73 (m, 4H) 2.08-2.24 (m, 1H) 4.09 (s,3H) 4.16 (s, 3H) 7.36 (d, J = 8.41 Hz, 1H) 7.96 (d, J = 8.41 Hz, 1H)8.05 (s, 1H) 8.13 (s, 1H) 8.27 (s, 1H) 8.54 (s, 1H); ESI m/z 402.2 [M +1]⁺ 38% 26 4-cyclopropyl-3-(5-(1- methyl-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)-1H- imidazol-4-yl)-1H-1,2,4- triazol-5(4H)-onehydrochloride

C ¹H NMR (400 MHz, CD₃OD) δ 0.60-0.76 (m, 4H) 2.07-2.18 (m, 1H) 4.16 (s,3H) 7.34-7.40 (m, 1H) 7.97 (d, J = 8.41 Hz, 1H) 8.02 (s, 1H) 8.14 (d, J= 0.75 Hz, 1H) 8.47 (s, 2H); ESI m/z 388.0 [M + 1]⁺ 36% 274-cyclopropyl-1-methyl- 3-(5-(1-methyl-1H- indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H- 1,2,4-triazol-5(4H)-one hydrochloride

D ¹H-NMR(DMSO-d₆, 300 MHz): δ 8.17 (d, J = 7.3 Hz, 2H), 8.09 (d, J = 9.2Hz, 2H), 7.77-7.85 (m, 1H), 7.44-7.62 (m, 3H), 7.27-7.34 (m, 1H), 4.08(s, 3H), 3.39 (s, 3H), 1.12-1.27 (m, 1H), 0.63 ppm (d, J = 4.5 Hz, 4H);ESI m/z 412.0 [M + 1]⁺ 20%

Example 28: Inhibition of Tetra-Acetylated histoneH4 Binding IndividualBET Bromodomains

Proteins were cloned and overexpressed with a N-terminal 6×His tag, thenpurified by nickel affinity followed by size exclusion chromatography.Briefly, E. coli BL21(DE3) cells were transformed with a recombinantexpression vector encoding N-terminally Nickel affinity taggedbromodomains from Brd2, Brd3, Brd4. Cell cultures were incubated at 37°C. with shaking to the appropriate density and induced overnight withIPTG. The supernatant of lysed cells was loaded onto Ni-IDA column forpurification. Eluted protein was pooled, concentrated and furtherpurified by size exclusion chromatography. Fractions representingmonomeric protein were pooled, concentrated, aliquoted, and frozen at−80° C. for use in subsequent experiments.

Binding of tetra-acetylated histone H4 peptide (Millipore) and BETbromodomains was confirmed by Amplified Luminescent Proximity HomogenousAssay (AlphaScreen). N-terminally His-tagged bromodomains (BRD4(1) at 20nM and BRD4(2) at 100 nM) and biotinylated tetra-acetylated histone H4(10-25 nM) were incubated in the presence of nickel chelate acceptorbeads and streptavidin donor beads (PerkinAlmer, 6760000K) added to afinal concentration of 2 μg/ml under green light in a white 96 wellmicrotiter plate (Greiner). For inhibition assays, serially dilutedcompounds were added to the reaction mixtures in a 0.1% finalconcentrations of DMSO. Final buffer concentrations were 50 mM HEPES,100 mM NaCl and 0.1% BSA buffer, pH 7.4 and optimized to 30 minincubation time. Assay plates were read at 570 nM on a Synergy H4 PlateReader (Biotek). IC₅₀ values were determined from a dose response curve.

Compounds with an IC₅₀ value less than or equal to 0.3 μM were deemed tobe highly active (+++); compounds with an IC₅₀ value between 0.3 and 3μM were deemed to be very active (++); compounds with an IC₅₀ valuebetween 3 and 30 μM were deemed to be active (+).

TABLE 3 Inhibition of Tetra-acetylated Histone H4 Binding to Brd4bromodomain 1 (BRD4(1)) and Brd 4 bromodomain 2 (BRD4(2)) Alpha AlphaAlpha Alpha Alpha Alpha Example Screen Screen Example Screen ScreenExample Screen Screen Number BRD4(1) BRD4(2) Number BRD4(1) BRD4(2)Number BRD4(1) BRD4(2) 1 +++ + 2 + + 3 + + 4 + Not Active 5 Not ActiveNot Active 6 ++ + 7 +++ Not Active 8 +++ Not Active 9 ++ Not Active 10 +++ 11 + Not Active 12 + ++ 13 ++ ++ 14 +++ +++ 15 ++ + 16 +++ ++ 17 NotActive Not Active 18 ++ + 19 ++ + 20 ++ + 21 + Not Active 22 + + 23+++ + 24 + + 25 ++ + 26 + + 27 + Not Active

Example 29: Inhibition of cMYC Expression in Cancer Cell Lines

MV4-11 cells (CRL-9591) were plated at a density of 2.5×10⁴ cells perwell in 96 well U-bottom plates and treated with increasingconcentrations of test compound or DMSO (0.1%) in IMDM media containing10% FBS and penicillin/streptomycin, and incubated for 3 h at 37° C.Triplicate wells were used for each concentration. Cells were pelletedby centrifugation and harvested using the mRNA Catcher PLUS kitaccording to manufacturer's instructions. The eluted mRNA isolated wasthen used in a one-step quantitative real-time PCR reaction, usingcomponents of the RNA UltraSense™ One-Step Kit (Life Technologies)together with Applied Biosystems TaqMan® primer-probes for cMYC andCyclophilin. Real-time PCR plates were run on a ViiA™7 real time PCRmachine (Applied Biosystems), data was analyzed, normalizing the Ctvalues for cMYC to an internal control, prior to determining the foldexpression of each sample, relative to the control.

Compounds with an IC₅₀ value less than or equal to 0.3 μM were deemed tobe highly active (+++); compounds with an IC₅₀ value between 0.3 and 3μM were deemed to be very active (++); compounds with an IC₅₀ valuebetween 3 and 30 μM were deemed to be active (+).

TABLE 4 Inhibition of c-myc Activity in Human AML MV4-11 cells Examplec-myc Example c-myc Example c-myc Example c-myc Number activity Numberactivity Number activity Number activity 1 + 2 Not Active 4 + 6 + 7 + 8Not Active 9 + 10 Not Active 13 + 14 + 18 Not Active 19 +

Example 30: Inhibition of Cell Proliferation in Cancer Cell Lines

MV4-11 cells (CRL-9591) were plated at a density of 5×10⁴ cells per wellin 96 well flat bottom plates and treated with increasing concentrationsof test compound or DMSO (0.1%) in IMDM media containing 10% FBS andpenicillin/streptomycin. Triplicate wells were used for eachconcentration and a well containing only media was used as a control.Plates were incubated at 37° C., 5% CO₂ for 72 h before adding 20 μL ofthe Cell Titer Aqueous One Solution (Promega) to each well and incubatedat 37° C., 5% CO₂ for an additional 3-4 h. The absorbance was read at490 nm in a spectrophotometer and the percentage of cell titer relativeto DMSO-treated cells was calculated after correcting for background bysubtracting the blank well's signal. IC₅₀ values were calculated usingthe GraphPad Prism software.

Compounds with an IC₅₀ value less than or equal to 0.3 μM were deemed tobe highly active (+++); compounds with an IC₅₀ value between 0.3 and 3μM were deemed to be very active (++); compounds with an IC₅₀ valuebetween 3 and 30 μM were deemed to be active (+).

TABLE 5 Inhibition of Cell Proliferation in Human AML MV-4-11 cells CellCell Cell Cell Example Proliferation Example Proliferation ExampleProliferation Example Proliferation Number activity Number activityNumber activity Number activity 1 + 2 Not Active 4 + 6 + 7 + 8 NotActive 9 + 10 Not Active 13 + 14 + − − − −

Example 31: Inhibition of hIL-6 mRNA Transcription

Human leukemic monocyte lymphoma U937 cells (CRL-1593.2) were plated ata density of 3.2×104 cells per well in a 96-well plate in 100 μLRPMI-1640 containing 10% FBS and penicillin/streptomycin, anddifferentiated into macrophages for 3 days in 60 ng/mL PMA(phorbol-13-myristate-12-acetate) at 37° C. in 5% CO₂ prior to theaddition of compound. The cells were pretreated for 1 h with increasingconcentrations of test compound in 0.1% DMSO prior to stimulation with 1ug/mL lipopolysaccharide from Escherichia coli. Triplicate wells wereused for each concentration. The cells were incubated at 37° C., 5% CO₂for 3 h before the cells were harvested. At time of harvest, media wasremoved and cells were rinsed in 200 μL PBS. Cells were harvested usingthe mRNA Catcher PLUS kit according to manufacturer's instructions. Theeluted mRNA was then used in a one-step quantitative real-time PCRreaction using components of the RNA UltraSense™ One-Step Kit (LifeTechnologies) together with Applied Biosystems TaqMan® primer-probes forhIL-6 and Cyclophilin. Real-time PCR plates were run on a ViiA™7 realtime PCR machine (Applied Biosystems), data was analyzed, normalizingthe Ct values for hIL-6 to an internal control, prior to determining thefold expression of each sample, relative to the control.

Compounds with an IC₅₀ value less than or equal to 0.3 μM were deemed tobe highly active (+++); compounds with an IC₅₀ value between 0.3 and 3μM were deemed to be very active (++); compounds with an IC₅₀ valuebetween 3 and 30 μM were deemed to be active J+).

TABLE 6 Inhibition of hIL-6 mRNA Transcription Example IL-6 Example IL-6Example IL-6 Example IL-6 Number activity Number activity Numberactivity Number activity 1 + 7 + 8 + 9 + 14 + − − − − − −

Examples 32: In Vivo Efficacy in Athymic Nude Mouse Strain of an AcuteMyeloid Leukemia Xenograft Model Using MV4-11 Cells

MV4-11 cells (ATCC) are grown under standard cell culture conditions and(NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected with5×10⁶ cells/animal in 100 μL PBS+100 μL Matrigel in the lower leftabdominal flank. By approximately day 18-21 after MV4-11 cellsinjection, mice are randomized based on tumor volume (L×W×H)/2) ofaverage ˜100-300 mm³. Mice are dosed orally with compound at 5 to 120mg/kg b.i.d and/or q.d. on a continuous dosing schedule and at 2.5 to 85mg/kg q.d. on a 5 day on 2 day off, 100 mg/kg q.d. on a 4 day on and 3day off, 135 mg/kg q.d. on a 3 day on and 4 day off, 180 mg/kg on a 2day on and 5 day off and 240 mg/kg on a 1 day on and 6 days off dosingschedules in EA006 formulation at 10 mL/kg body weight dose volume.Tumor measurements are taken with electronic micro calipers and bodyweights measured on alternate days beginning from dosing period. Theaverage tumor volumes, percent Tumor Growth Inhibition (TGI) and %change in body weights are compared relative to Vehicle control animals.The means, statistical analysis and the comparison between groups arecalculated using Student's t-test in Excel.

Other embodiments of the present disclosure will be apparent to thoseskilled in the art from consideration of the specification and practiceof the present disclosure disclosed herein. It is intended that thespecification and examples be considered as exemplary only, with a truescope and spirit of the present disclosure being indicated by thefollowing claims.

What is claimed is:
 1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein: X is selected from CH and N; Y is selectedfrom —NH, —N—R_(1b) and oxygen; Z is selected from N, and —CH—; R_(1a)and R_(1b) are independently selected from (C₁-C₆)alkyl,(C₃-C₁₀)carbocycle, and (C₂-C₁₀)heterocycle, each of which may beoptionally substituted with 1 to 3 groups selected from R₄; R₂ isselected from (C₅-C₁₀)aryl and (C₅-C₁₀)heteroaryl, each of which may beoptionally substituted with 1 to 5 groups selected from R₅; R₃ isselected from (C₃-C₁₀) carbocycle and (C₂-C₁₀)heterocycle, each of whichmay be optionally substituted with 1 to 5 groups selected from R₅; eachR₄ is independently selected from deuterium, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₁-C₆)alkoxy, amino, —NHC(O)NH—(C₁-C₆)alkyl,halogen, amide, —CF₃, —CN, —N₃, ketone, —S(O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, thio-(C₁-C₆)alkyl, —COOH, and ester, each of whichmay be optionally substituted with F, Cl, Br, —OH, —NH₂, —NHMe, —OMe,—SMe, oxo, and/or thio-oxo; and each R₅ is independently selected fromdeuterium, (C₁-C₅)alkyl, (C₁-C₆)alkoxy, amino, —NHC(O)NH—(C₁-C₆)alkyl,halogen, amide, —CF₃, —CN, —N₃, (C₁-C₆) ketone, —S(O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, thio-(C₁-C₆)alkyl, —COOH, and ester, each of whichmay be optionally substituted with F, Cl, Br, —OH, —NH₂, —NHMe, —OMe,—SMe, oxo, and/or thio-oxo.
 2. A compound according to claim 1, whereinthe compound is a compound of Formula Ia:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein: R_(1a) is selected from (C₁-C₆)alkyl,(C₃-C₁₀)carbocycle, and (C₂-C₁₀)heterocycle, each of which may beoptionally substituted with 1 to 3 groups selected from R₄; R₂ isselected from (C₅-C₁₀)aryl and (C₅-C₁₀)heteroaryl, each of which may beoptionally substituted with 1 to 5 groups selected from R₅; R₃ isselected from (C₃-C₁₀) carbocycle and (C₂-C₁₀)heterocycle, each of whichmay be optionally substituted with 1 to 5 groups selected from R₅; eachR₄ is independently selected from deuterium, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₁-C₆)alkoxy, amino, —NHC(O)NH—(C₁-C₆)alkyl,halogen, amide, —CF₃, —CN, —N₃, ketone, —S(O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, thio-(C₁-C₆)alkyl, —COOH, and ester, each of whichmay be optionally substituted with F, Cl, Br, —OH, —NH₂, —NHMe, —OMe,—SMe, oxo, and/or thio-oxo; and each R₅ is independently selected fromdeuterium, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, —NHC(O)NH—(C₁-C₆)alkyl,halogen, amide, —CF₃, —CN, —N₃, (C₁-C₆)ketone, —S(O)—(C₁-C₄)alkyl,—SO₂—(C₁-C₆)alkyl, thio-(C₁-C₆)alkyl, —COOH, and ester, each of whichmay be optionally substituted with F, Cl, Br, —OH, —NH₂, —NHMe, —OMe,—SMe, oxo, and/or thio-oxo.
 3. The compound according to claim 1,wherein Y is —NR_(1b).
 4. The compound according to claim 2, whereinR_(1a) is selected from the following structures,

each of which may be optionally substituted with 1 to 3 groups selectedfrom R₄, and

each of which may be optionally substituted with F, Cl, Br, —OH, —NH₂,—NHMe, —OMe, —SMe, oxo, and/or thio-oxo.
 5. The compound according toclaim 4, wherein R_(1a) is selected from the following structures:

each of which may be optionally substituted with 1 to 3 groups selectedfrom R₄, and

which may be optionally substituted with F, Cl, Br, —OH, —NH₂, —NHMe,—OMe, —SMe, oxo, and/or thio-oxo.
 6. The compound according to claim 5,wherein R_(1a) is


7. The compound according to claim 2, wherein R_(1a) is selected fromthe following structures, which may be optionally substituted with 1 to3 groups selected from R₄:


8. The compound according to claim 3, wherein R_(1b) is (C₁-C₆)alkyl. 9.The compound according to claim 8, wherein R_(1b) is selected frommethyl and ethyl.
 10. The compound according to claim 2, wherein R₂ isselected from bicyclic (C₅-C₁₀)aryl and bicyclic (C₅-C₁₀)heteroarylgroups optionally substituted with 1 to 5 R₅ groups.
 11. The compoundaccording to claim 2, wherein R₂ is selected from the following:

each of which may be optionally substituted with 1 to 2 groups selectedfrom (C₁-C₆)alkyl, halogen, ketone, amide, and ester, and

which may be optionally substituted with F, Cl, Br, —OH, —NH₂, —NHMe,—OMe, —SMe, oxo, and/or thio-oxo.
 12. The compound according to claim11, wherein R₂ is


13. The compound according to claim 2, wherein R₃ is selected from thefollowing structures:

each of which may be optionally substituted with 1 to 5 groups selectedfrom R₅.
 14. The compound according to claim 13, wherein R₃ is selectedfrom the following structures:

each of which may be optionally substituted with 1 to 5 groups selectedfrom R₅.
 15. The compound according to claim 14, wherein R₃ is anunsubstituted phenyl group.
 16. A compound selected from:3-(5-(3-Acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;Methyl3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-4-methylbenzoate;3-(4-(4-Cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-N-methylbenzamide;3-(4-(4-Cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)benzamide;4-Cyclopropyl-3-(5-(3-oxo-2,3-dihydro-1H-inden-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-3-(2-phenyl-5-(3-propionylphenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;3-(5-(3-Acetyl-4-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;3-(5-(3-Acetyl-5-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;4-cyclopropyl-3-(5-(1-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;3-(5-(5-acetyl-2-methylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;3-(5-(5-acetylpyridin-3-yl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-oneformate;4-cyclopropyl-3-(5-(1,3-dimethyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-(Cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Isopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-(tert-Butyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopentyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclobutyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclohexyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Isobutyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;3-(5-(1-Methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-4-neopentyl-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-1-methyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-1-ethyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-1-(cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-1-(2-methoxyethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-3-(5-(3-methylbenzo[d]isoxazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-3-(5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-3-(5-(3-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-3-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;3-(2-(1H-Indol-6-yl)-5-(1-methyl-1H-indazol-6-yl)-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;and stereoisomers, tautomers, pharmaceutically acceptable salts, andhydrates thereof.
 17. A compound is selected from:3-(5-(3-acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-onehydrochloride; methyl3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-4-methylbenzoate hydrochloride;3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-N-methylbenzamide hydrochloride;3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)benzamidehydrochloride;4-cyclopropyl-3-(5-(3-oxo-2,3-dihydro-1H-inden-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride;4-cyclopropyl-3-(2-phenyl-5-(3-propionylphenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride;4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride;3-(5-(3-acetyl-4-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-onehydrochloride;3-(5-(3-acetyl-5-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-onehydrochloride;4-cyclopropyl-3-(5-(1-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride;3-(5-(5-acetyl-2-methylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-onehydrochloride;4-cyclopropyl-3-(5-(3-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride;4-cyclopropyl-3-(5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride;4-cyclopropyl-3-(5-(1,3-dimethyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride;4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onedihydrochloride;4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-3-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onedihydrochloride;4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride;4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one6hydrochloride;4-cyclopropyl-1-methyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-onehydrochloride; and stereoisomers, tautomers, and hydrates thereof.
 18. Apharmaceutical composition comprising the compound of claim 1, and apharmaceutically acceptable carrier.
 19. A method for inhibition of BETprotein function comprising administering a therapeutically effectiveamount of the compound of claim 1 to a mammal in need thereof.
 20. Amethod of treating a disease or disorder comprising administering atherapeutically effective amount of the compound according to claim 1 toa mammal in need thereof slam-96, wherein the disease or disorder isselected from Acute Disseminated Encephalomyelitis, Agammaglobulinemia,Allergic Disease, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis,Anti-phospholipid syndrome, Autoimmune aplastic anemia, Autoimmunehepatitis, Autoimmune inner ear disease, Autoimmune myocarditis,Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmunethrombocytopenic purpura, Behcet's Disease, Bullous pemphigoid,Castleman's Disease, Celiac Disease, Churg-Strauss syndrome, Crohn'sDisease, Cogan's syndrome, Dry eye syndrome, Essential mixedcryoglobulinemia, Dermatomyositis, Devic's Disease, Encephalitis,Eosinophlic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giantcell arteritis, Glomerulonephritis, Goodpasture's syndrome,Granulomatosis with Polyangiitis (Wegener's), Graves' Disease,Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia,Henoch-Schonlein purpura, idiopathic pulmonary fibrosis, IgAnephropathy; Inclusion body myositis, Type I diabetes, Interstitialcystitis, Kawasaki's Disease, Leukocytoclastic vasculitis, Lichenplanus, Lupus (SLE), Microscopic polyangitis, Multiple sclerosis,Myasthenia gravis, myositis, Optic neuritis, Pemphigus, POEMS syndrome,Polyarteritis nodosa, Primary biliary cirrhosis, Psoriasis, Psoriaticarthritis, Pyoderma gangrenosum, Relapsing polychondritis, Rheumatoidarthritis, Sarcoidosis, Scleroderma, Sjogren's syndrome, Takayasu'sarteritis, Transverse myelitis, Ulcerative colitis, Uveitis, Vitiligo,sinusitis, pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis,appendicitis, irritable bowel syndrome, tissue graft rejection, chronicobstructive pulmonary disease (COPD), septic shock, osteoarthritis,acute gout, acute lung injury, acute renal failure, burns, Herxheimerreaction, and SIRS associated with viral infections, comprisingadministering a therapeutically effective amount of the compoundaccording to claim 1 to a mammal in need thereof.
 21. A method oftreating cancer comprising administering a therapeutically effectiveamount of the compound according to claim 1 to a mammal in need thereof,wherein the cancer is selected from Burkitt's lymphoma, Hodgkin'slymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma,follicular lymphoma, multiple myeloma, bladder cancer, breast cancer,colon cancer, melanoma, ovarian cancer, prostate cancer, small cell lungcarcinoma, non-small cell lung cancer, NUT midline carcinoma, acuteB-cell lymphoma, and head and neck squamous cell carcinoma.
 22. A methodof treating cancer comprising administering a therapeutically effectiveamount of the compound according to claim 1 to a mammal in need thereof,wherein said cancer: is associated with overexpression, translocation,amplification, or rearrangement of a myc family oncoprotein and isselected from B-acute lymphocytic leukemia, Burkitt's lymphoma, Diffuselarge B-cell lymphoma, Multiple myeloma, Primary plasma cell leukemia,Atypical carcinoid lung cancer, Bladder cancer, Breast cancer, Cervixcancer, Colon cancer, Gastric cancer, Glioblastoma, Hepatocellularcarcinoma, Large cell neuroendocrine carcinoma, Medulloblastoma,Melanoma, nodular, Melanoma, superficial spreading, Neuroblastoma,esophageal squamous cell carcinoma, Osteosarcoma, Ovarian cancer,Prostate cancer, Renal clear cell carcinoma, Retinoblastoma,Rhabdomyosarcoma, and Small cell lung carcinoma; is associated withoverexpression, translocation, amplification, or rearrangement of BETproteins and is selected from NUT midline carcinoma, B-cell lymphoma,non-small cell lung cancer, esophageal cancer, head and neck squamouscell carcinoma, breast cancer, prostate cancer, and colon cancer; thatrelies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenesand is selected from chronic lymphocytic leukemia, multiple myeloma,follicular lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma,Hodgkin's lymphoma, anaplastic large cell lymphoma, neuroblastoma andprimary neuroectodermal tumor, rhabdomyosarcoma, prostate cancer, andbreast cancer; is associated with upregulation of BET responsive genesCDK6, Bcl2, TYRO3, MYB, and hTERT is selected from pancreatic cancer,breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma,T-cell prolymphocytic leukemia, malignant glioma, bladder cancer,medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barret'sadenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia,chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-celllymphoma, small cell lung cancer, and renal carcinoma; is sensitive toeffects of BET inhibition is selected from NUT-midline carcinoma (NMV),acute myeloid leukemia (AML), acute B lymphoblastic leukemia (B-ALL),Burkitt's Lymphoma, acute B-cell Lymphoma, Melanoma, mixed lineageleukemia, multiple myeloma, pro-myelocytic leukemia (PML), non-Hodgkin'slymphoma, Neuroblastoma, Medulloblastoma, lung carcinoma (NSCLC, SCLC),breast cancer, prostate cancer, and colon carcinoma; and/or isassociated with a virus selected from Epstein-Barr Virus (EBV),hepatitis B virus (HBV), hepatitis C virus (HCV), Kaposi's sarcomaassociated virus (KSHV), human papilloma virus (HPV), Merkel cellpolyomavirus, and human cytomegalovirus (CMV).
 23. A method of treatingcancer comprising administering a therapeutically effective amount ofthe compound according to claim 1 to a mammal in need thereof, whereinsaid cancer is associated with the MYC oncogene.
 24. The method of claim21, wherein the cancer is resistant to treatment with immunotherapy,hormone-deprivation therapy, and/or chemotherapy.
 25. The method ofclaim 21, wherein administration of a therapeutically effective amountof said compound: restores sensitivity to immunotherapy,hormone-deprivation therapy, and/or chemotherapy; and/or inhibitsproliferation of cancer cells, and/or induces cancer cell death orsenescence.
 26. The method of claim 21, wherein said compound iscombined with other therapies, chemotherapeutic agents, orantiproliferative agents.
 27. A method of treating a benignproliferative or fibrotic disorder selected from benign soft tissuetumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors,granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasalpolyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheickeratoses, stomach polyps, thyroid nodules, cystic neoplasms of thepancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castlemandisease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenicgranuloma, juvenile polyposis syndrome, idiopathic pulmonary fibrosis,renal fibrosis, post-operative stricture, keloid formation, scleroderma,and cardiac fibrosis, comprising administering a therapeuticallyeffective amount of the compound of claim 1 to a mammal in need thereof.28. A method of treating a disease or disorder comprising administeringa therapeutically effective amount of the compound according to claim 1to a mammal in need thereof, wherein said disease or disorder isselected from: cardiovascular disease, dyslipidemia, atherosclerosis,hypercholesterolemia, metabolic syndrome, Alzheimer's disease,obesity-associated inflammation, type II diabetes, insulin resistance,Alzheimer's disease, Parkinson's disease, Huntington disease, bipolardisorder, schizophrenia, Rubinstein-Taybi syndrome, and epilepsy.
 29. Apharmaceutical composition comprising the compound of claim 16, and apharmaceutically acceptable carrier.
 30. A pharmaceutical compositioncomprising the compound of claim 17, and a pharmaceutically acceptablecarrier.